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  • Review Article
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Prospects for pharmacological targeting of pseudokinases

Abstract

Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of human diseases, yet they remain largely unexplored as drug targets owing to challenges associated with modulation of their biological functions. Our understanding of the structure and physiological roles of pseudokinases has improved substantially over the past decade, revealing intriguing similarities between pseudokinases and their catalytically active counterparts. Pseudokinases often adopt conformations that are analogous to those seen in catalytically active kinases and, in some cases, can also bind metal cations and/or nucleotides. Several clinically approved kinase inhibitors have been shown to influence the noncatalytic functions of active kinases, providing hope that similar properties in pseudokinases could be pharmacologically regulated. In this Review, we discuss known roles of pseudokinases in disease, their unique structural features and the progress that has been made towards developing pseudokinase-directed therapeutics.

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Fig. 1: Prevalence of pseudokinases in the kinomes of diverse species.
Fig. 2: Dysregulation of pseudokinase signalling in disease.
Fig. 3: Structural features of pseudokinases.
Fig. 4: Accessibility of the putative nucleotide-binding pocket in different classes of pseudokinases.
Fig. 5: Strategies for pharmacological targeting of pseudokinases.

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References

  1. Futreal, P. A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu, P., Nielsen, T. E. & Clausen, M. H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 36, 422–439 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Creixell, P. et al. Kinome-wide decoding of network-attacking mutations rewiring cancer signaling. Cell 163, 202–217 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chang, M. T. et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat. Biotechnol. 34, 155–163 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Nieto, P. et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548, 239–243 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wan, P. T. C. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Garnett, M. J. et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 20, 963–969 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Yao, Z. et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548, 234–238 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jacobsen, A. V. & Murphy, J. M. The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases. Biochem. Soc. Trans. 45, 665–681 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Kung, J. E. & Jura, N. Structural basis for the non-catalytic functions of protein kinases. Structure 24, 7–24 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaw, A. S., Kornev, A. P., Hu, J., Ahuja, L. G. & Taylor, S. S. Kinases and pseudokinases: lessons from RAF. Mol. Cell. Biol. 34, 1538–1546 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Mandal, P. et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56, 481–495 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Camps, M. et al. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science 280, 1262–1265 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Zhou, B. et al. Mapping ERK2-MKP3 binding interfaces by hydrogen/deuterium exchange mass spectrometry. J. Biol. Chem. 281, 38834–38844 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Reiterer, V., Eyers, P. A. & Farhan, H. Day of the dead: pseudokinases and pseudophosphatases in physiology and disease. Trends Cell Biol. 24, 489–505 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Bailey, F. P., Byrne, D. P., McSkimming, D., Kannan, N. & Eyers, P. A. Going for broke: targeting the human cancer pseudokinome. Biochem. J. 465, 195–211 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Caenepeel, S., Charydczak, G., Sudarsanam, S., Hunter, T. & Manning, G. The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc. Natl Acad. Sci. USA 101, 11707–11712 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Castells, E. & Casacuberta, J. M. Signalling through kinase-defective domains: the prevalence of atypical receptor-like kinases in plants. J. Exp. Bot. 58, 3503–3511 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Bemm, F., Schwarz, R., Förster, F. & Schultz, J. A kinome of 2600 in the ciliate Paramecium tetraurelia. FEBS Lett. 583, 3589–3592 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Goldberg, J. M. et al. The dictyostelium kinome—analysis of the protein kinases from a simple model organism. PLOS Genet. 2, e38 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Peixoto, L. et al. Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses. Cell Host Microbe 8, 208–218 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hunter, T. & Manning, G. in Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease (eds Wheeler, D. L. & Yarden, Y.) 1–15 (Springer, New York, NY, 2015).

  28. Wilson, L. J. et al. New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Res. 78, 15–29 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Byrne, D. P., Foulkes, D. M. & Eyers, P. A. Pseudokinases: update on their functions and evaluation as new drug targets. Future Med. Chem. 9, 245–265 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Jura, N., Shan, Y., Cao, X., Shaw, D. E. & Kuriyan, J. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc. Natl Acad. Sci. USA 106, 21608–21613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Monsey, J., Shen, W., Schlesinger, P. & Bose, R. Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system. J. Biol. Chem. 285, 7035–7044 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Littlefield, P. et al. Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations. Sci. Signal. 7, ra114 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137–1149 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, L. et al. Regulation of kinase activity in the Caenorhabditis elegans EGF receptor, LET-23. Structure 26, 270–281 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, K. et al. Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J. Biol. Chem. 271, 3884–3890 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Hellyer, N. J., Kim, M. S. & Koland, J. G. Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J. Biol. Chem. 276, 42153–42161 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Erjala, K. et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin. Cancer Res. 12, 4103–4111 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437–441 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Miller, T. W. et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 69, 4192–4201 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Desbois-Mouthon, C. et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin. Cancer Res. 15, 5445–5456 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Jeong, E. G. et al. ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas. Int. J. Cancer 119, 2986–2987 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

    Article  CAS  Google Scholar 

  47. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

    Article  CAS  Google Scholar 

  48. Jaiswal, B. S. et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23, 603–617 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Mishra, R. et al. Activating HER3 mutations in breast cancer. Oncotarget 9, 27773–27788 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Riethmacher, D. et al. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 725–730 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Massa, R. et al. Overexpression of ErbB2 and ErbB3 receptors in Schwann cells of patients with Charcot-Marie-tooth disease type 1A. Muscle Nerve 33, 342–349 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Kanazawa, T. et al. Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 113–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Watanabe, Y. et al. No association between the ERBB3 gene and schizophrenia in a Japanese population. Neurosci. Res. 57, 574–578 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Al-Shawi, R., Ashton, S. V., Underwood, C. & Simons, J. P. Expression of the Ror1 and Ror2 receptor tyrosine kinase genes during mouse development. Dev. Genes Evol. 211, 161–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Fukuda, T. et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc. Natl Acad. Sci. USA 105, 3047–3052 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Oishi, I. et al. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8, 645–654 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Yu, J. et al. Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation. J. Clin. Invest. 126, 585–598 (2016).

    Article  PubMed  Google Scholar 

  58. Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P. M. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71, 3132–3141 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P. M. The ROR1 pseudokinase diversifies signaling outputs in MET-addicted cancer cells. Int. J. Cancer 135, 2305–2316 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Yamaguchi, T. et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 21, 348–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Morioka, K. et al. Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma. Cancer Sci. 100, 1227–1233 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Wright, T. M. et al. Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene 28, 2513–2523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lara, E. et al. Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer. Mol. Cancer 9, 170 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Geng, M. et al. Loss of Wnt5a and Ror2 protein in hepatocellular carcinoma associated with poor prognosis. World J. Gastroenterol. 18, 1328–1338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mikels, A. J. & Nusse, R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLOS Biol. 4, e115 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Oldridge, M. et al. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat. Genet. 24, 275–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Schwabe, G. C. et al. Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Am. J. Hum. Genet. 67, 822–831 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Afzal, A. R. et al. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat. Genet. 25, 419–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. van Bokhoven, H. et al. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat. Genet. 25, 423–426 (2000).

    Article  PubMed  CAS  Google Scholar 

  70. Schwabe, G. C. et al. Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome. Dev. Dyn. 229, 400–410 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Peradziryi, H. et al. PTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling. EMBO J. 30, 3729–3740 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Martinez, S. et al. The PTK7 and ROR2 protein receptors interact in the vertebrate WNT/planar cell polarity (PCP) pathway. J. Biol. Chem. 290, 30562–30572 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wehner, P. et al. RACK1 is a novel interaction partner of PTK7 that is required for neural tube closure. Development 138, 1321–1327 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Puppo, F. et al. Protein tyrosine kinase 7 has a conserved role in Wnt/β-catenin canonical signalling. EMBO Rep. 12, 43–49 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Hayes, M. et al. ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease. Nat. Commun. 5, 4777 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Wang, M. et al. Role of the planar cell polarity gene protein tyrosine kinase 7 in neural tube defects in humans. Birth Defects Res. A Clin. Mol. Teratol. 103, 1021–1027 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Mossie, K. et al. Colon carcinoma kinase-4 defines a new subclass of the receptor tyrosine kinase family. Oncogene 11, 2179–2184 (1995).

    CAS  PubMed  Google Scholar 

  78. Chen, R. et al. A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma. Cancer Res. 74, 2892–2902 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gärtner, S. et al. PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement. PLOS ONE 9, e84472 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Wang, H. et al. PTK7 protein is decreased in epithelial ovarian carcinomas with poor prognosis. Int. J. Clin. Exp. Pathol. 7, 7881–7889 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Easty, D. J. et al. Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma. Int. J. Cancer 71, 1061–1065 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Lu, W., Yamamoto, V., Ortega, B. & Baltimore, D. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119, 97–108 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Keeble, T. R. et al. The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum. J. Neurosci. 26, 5840–5848 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu, Y. et al. Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nat. Neurosci. 8, 1151–1159 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, Y. et al. Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J. Neurosci. 28, 8376–8382 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Katso, R. M. et al. Overexpression of H-Ryk in epithelial ovarian cancer: prognostic significance of receptor expression. Clin. Cancer Res. 6, 3271–3281 (2000).

    CAS  PubMed  Google Scholar 

  87. Saharinen, P., Takaluoma, K. & Silvennoinen, O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol. 20, 3387–3395 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Saharinen, P. & Silvennoinen, O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J. Biol. Chem. 277, 47954–47963 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Walters, D. K. et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10, 65–75 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Flex, E. et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205, 751–758 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jeong, E. G. et al. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin. Cancer Res. 14, 3716–3721 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Lupardus, P. J. et al. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl Acad. Sci. USA 111, 8025–8030 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. Shan, Y. et al. Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nat. Struct. Mol. Biol. 21, 579–584 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, M. et al. Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: evidence for interactions between the kinase and pseudokinase domains. Mol. Cell. Biol. 20, 947–956 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li, Z. et al. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J. Immunol. 190, 2335–2344 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Hildebrand, J. M. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl Acad. Sci. USA 111, 15072–15077 (2014). This study identifies an ATP-competitive compound that binds to the pseudoactive site of MLKL and inhibits necroptosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ting, A. T., Pimentel-Muiños, F. X. & Seed, B. RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. EMBO J. 15, 6189–6196 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rajakulendran, T. et al. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461, 542–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Hu, J. et al. Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF. Proc. Natl Acad. Sci. USA 108, 6067–6072 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lavoie, H. et al. MEK drives BRAF activation through allosteric control of KSR proteins. Nature 554, 549–553 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lozano, J. et al. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 63, 4232–4238 (2003).

    CAS  PubMed  Google Scholar 

  106. Kortum, R. L. & Lewis, R. E. The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Mol. Cell. Biol. 24, 4407–4416 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nguyen, A. et al. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell. Biol. 22, 3035–3045 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Costanzo-Garvey, D. L. et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 10, 366–378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Revelli, J.-P. et al. Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. Obesity (Silver Spring) 19, 1010–1018 (2011).

    Article  CAS  Google Scholar 

  110. Pearce, L. R. et al. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell 155, 765–777 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tagliabracci, V. S. et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science 336, 1150–1153 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cui, J. et al. A secretory kinase complex regulates extracellular protein phosphorylation. eLife 4, e06120 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Ohyama, Y. et al. FAM20A binds to and regulates FAM20C localization. Sci. Rep. 6, 27784 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. O’Sullivan, J. et al. Whole-exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. Am. J. Hum. Genet. 88, 616–620 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Simpson, M. A. et al. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am. J. Hum. Genet. 81, 906–912 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tagliabracci, V. S. et al. A single kinase generates the majority of the secreted phosphoproteome. Cell 161, 1619–1632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dedhia, P. H. et al. Differential ability of Tribbles family members to promote degradation of C/EBPα and induce acute myelogenous leukemia. Blood 116, 1321–1328 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Qi, L. et al. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312, 1763–1766 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Keeshan, K. et al. Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding. Blood 116, 4948–4957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jamieson, S. A. et al. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Sci. Signal. 11, eaau0597 (2018). This study demonstrates that substrate binding alters the conformation of the TRIB1 pseudokinase domain, providing evidence that pseudokinases can undergo conformational transitions similar to those observed for active kinases.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Eyers, P. A., Keeshan, K. & Kannan, N. Tribbles in the 21st century: the evolving roles of Tribbles pseudokinases in biology and disease. Trends Cell Biol. 27, 284–298 (2016).

    Article  PubMed  CAS  Google Scholar 

  122. Yoshida, A., Kato, J.-Y., Nakamae, I. & Yoneda-Kato, N. COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1. Blood 122, 1750–1760 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Bauer, R. C., Yenilmez, B. O. & Rader, D. J. Tribbles-1: a novel regulator of hepatic lipid metabolism in humans. Biochem. Soc. Trans. 43, 1079–1084 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yokoyama, T. et al. Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis. Blood 116, 2768–2775 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Izrailit, J., Berman, H. K., Datti, A., Wrana, J. L. & Reedijk, M. High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer. Proc. Natl Acad. Sci. 110, 1714–1719 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Du, K., Herzig, S., Kulkarni, R. N. & Montminy, M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300, 1574–1577 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Liew, C. W. et al. The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells. J. Clin. Invest. 120, 2876–2888 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zareen, N. et al. A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons. Cell Death Differ. 20, 1719–1730 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Aimé, P. et al. Trib3 is elevated in Parkinson’s disease and mediates death in Parkinson’s disease models. J. Neurosci. 35, 10731–10749 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Hill, R. et al. TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Nat. Commun. 8, 14687 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  131. McMahon, S. B., Van Buskirk, H. A., Dugan, K. A., Copeland, T. D. & Cole, M. D. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94, 363–374 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Deleu, L., Shellard, S., Alevizopoulos, K., Amati, B. & Land, H. Recruitment of TRRAP required for oncogenic transformation by E1A. Oncogene 20, 8270–8275 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Martinez, E. et al. Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Mol. Cell. Biol. 21, 6782–6795 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Brand, M., Yamamoto, K., Staub, A. & Tora, L. Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction. J. Biol. Chem. 274, 18285–18289 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. McMahon, S. B., Wood, M. A. & Cole, M. D. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol. Cell. Biol. 20, 556–562 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lang, S. E., McMahon, S. B., Cole, M. D. & Hearing, P. E2F transcriptional activation requires TRRAP and GCN5 cofactors. J. Biol. Chem. 276, 32627–32634 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Lang, S. E. & Hearing, P. The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex. Oncogene 22, 2836–2841 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Park, J., Kunjibettu, S., McMahon, S. B. & Cole, M. D. The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis. Genes Dev. 15, 1619–1624 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Huse, M. & Kuriyan, J. The conformational plasticity of protein kinases. Cell 109, 275–282 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Taylor, S. S. & Kornev, A. P. Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem. Sci. 36, 65–77 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Jura, N. et al. Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol. Cell 42, 9–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Murphy, J. M. et al. Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure 23, 2111–2121 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Ha, B. H. & Boggon, T. J. The crystal structure of pseudokinase PEAK1 (Sugen Kinase 269) reveals an unusual catalytic cleft and a novel mode of kinase fold dimerization. J. Biol. Chem. 293, 1642–1650 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Patel, O. et al. Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association. Nat. Commun. 8, 1157 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Lecointre, C. et al. Dimerization of the pragmin pseudo-kinase regulates protein tyrosine phosphorylation. Structure 26, 545–554 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Scheeff, E. D., Eswaran, J., Bunkoczi, G., Knapp, S. & Manning, G. Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site. Structure 17, 128–138 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hari, S. B., Merritt, E. A. & Maly, D. J. Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases. Chem. Biol. 21, 628–635 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Han, Y. et al. Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response. Science 343, 1244–1248 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Huang, H. et al. Dimeric structure of pseudokinase RNase L bound to 2-5A reveals a basis for interferon-induced antiviral activity. Mol. Cell 53, 221–234 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Shi, F. et al. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc. Natl Acad. Sci. USA 107, 7692–7697 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zeqiraj, E. et al. ATP and MO25α regulate the conformational state of the STRADα pseudokinase and activation of the LKB1 tumour suppressor. PLOS Biol. 7, e1000126 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Zeqiraj, E., Filippi, B. M., Deak, M., Alessi, D. R. & van Aalten, D. M. F. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science 326, 1707–1711 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Artim, S. C., Mendrola, J. M. & Lemmon, M. A. Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochem. J. 448, 213–220 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Xie, T. et al. Structural insights into RIP3-mediated necroptotic signaling. Cell Rep. 5, 70–78 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Murphy, J. M. et al. Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL. Biochem. J. 457, 369–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Ma, B. et al. ATP-competitive MLKL binders have no functional impact on necroptosis. PLOS ONE 11, e0165983 (2016). This paper reveals that a previously identified ATP-competitive inhibitor of MLKL stabilizes the pseudokinase domain in the DFG-out state. This compound is also found to inhibit RIPK1, while ATP-competitive molecules that bind to MLKL with greater specificity are unable to inhibit necroptosis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Pearce, L. R., Komander, D. & Alessi, D. R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9–22 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Murphy, J. M. et al. A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties. Biochem. J. 457, 323–334 (2013). In this study, a wide range of pseudokinases are classified into different classes on the basis of their ability to bind nucleotides and/or cations.

    Article  CAS  Google Scholar 

  160. Gee, C. L. et al. A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci. Signal. 5, ra7 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Zheng, J. et al. 2.2A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr. D Biol. Crystallogr. 49, 362–365 (1993).

    Article  CAS  PubMed  Google Scholar 

  162. Bailey, F. P. et al. The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner. Biochem. J. 467, 47–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Mukherjee, K. et al. CASK functions as a Mg2+-independent neurexin kinase. Cell 133, 328–339 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Cui, J. et al. Structure of Fam20A reveals a pseudokinase featuring unique disulfide pattern and inverted ATP-binding. eLife 6, e23990 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Labesse, G. et al. ROP2 from Toxoplasma gondii: a virulence factor with a protein-kinase foldand no enzymatic activity. Structure 17, 139–146 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Qiu, W. et al. Novel structural and regulatory features of rhoptry secretory kinases in Toxoplasma gondii. EMBO J. 28, 969–979 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Brady, D. C. et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509, 492–496 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Mendrola, J. M., Shi, F., Park, J. H. & Lemmon, M. A. Receptor tyrosine kinases with intracellular pseudokinase domains. Biochem. Soc. Trans. 41, 1029–1036 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ungureanu, D. et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol. 18, 971–976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hammarén, H. M. et al. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc. Natl Acad. Sci. USA 112, 4642–4647 (2015). This paper demonstrates that ATP binding to the JH2 pseudokinase domain of JAK2 is essential for hyperactivation of pathogenic JAK2 mutants.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  171. Bandaranayake, R. M. et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat. Struct. Mol. Biol. 19, 754–759 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Brennan, D. F. et al. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature 472, 366–369 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Cameron, A. J. M. & Cameron, A. J. M. Occupational hazards: allosteric regulation of protein kinases through the nucleotide-binding pocket. Biochem. Soc. Trans. 39, 472–476 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Dar, A. C. & Shokat, K. M. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu. Rev. Biochem. 80, 769–795 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. Claus, J., Cameron, A. J. M. & Parker, P. J. Pseudokinase drug intervention: a potentially poisoned chalice. Biochem. Soc. Trans. 41, 1083–1088 (2013).

    Article  CAS  PubMed  Google Scholar 

  176. Karoulia, Z., Gavathiotis, E. & Poulikakos, P. I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 17, 676–691 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  178. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Karoulia, Z. et al. An integrated model of RAF inhibitor action predicts inhibitor activity against oncogenic BRAF signaling. Cancer Cell 30, 485–498 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Jin, T. et al. RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition. Nat. Comms 8, 1211 (2017).

    Article  CAS  Google Scholar 

  182. Zhang, C. et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526, 583–586 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Okimoto, R. A. et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc. Natl Acad. Sci. USA 113, 13456–13461 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Girotti, M. R. et al. Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell 27, 85–96 (2014).

    Article  PubMed  CAS  Google Scholar 

  185. Mendez, A. S. et al. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. eLife 4, e05434 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  186. Papa, F. R., Zhang, C., Shokat, K. & Walter, P. Bypassing a kinase activity with an ATP-competitive drug. Science 302, 1533–1537 (2003).

    Article  CAS  PubMed  Google Scholar 

  187. Korennykh, A. V. et al. The unfolded protein response signals through high-order assembly of Ire1. Nature 457, 687–693 (2009).

    Article  CAS  PubMed  Google Scholar 

  188. Wang, L. et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat. Chem. Biol. 8, 982–989 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ghosh, R. et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158, 534–548 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Waller, D. D. et al. A covalent cysteine-targeting kinase inhibitor of Ire1 permits allosteric control of endoribonuclease activity. Chembiochem 17, 843–851 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Otto, T. et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  192. Brockmann, M. et al. Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-Myc in childhood neuroblastoma. Cancer Cell 24, 75–89 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Gustafson, W. C. et al. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell 26, 414–427 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Claus, J. et al. Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface. eLife 7, e32271 (2018). This study reveals that the HER2 inhibitor lapatinib promotes heterodimerization of HER2 and HER3 through their N-lobes. This study also demonstrates that ATP binding is essential for the allosteric activator function of HER3 and that bosutinib enhances this function.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Wood, E. R. et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 64, 6652–6659 (2004).

    Article  CAS  PubMed  Google Scholar 

  196. Qiu, C. et al. Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 16, 460–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Huang, Y. et al. Molecular basis for multimerization in the activation of the epidermal growth factor receptor. eLife 5, e14107 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Liang, S. I. et al. Phosphorylated EGFR dimers are not sufficient to activate Ras. Cell Rep. 22, 2593–2600 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Dhawan, N. S., Scopton, A. P. & Dar, A. C. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling. Nature 537, 112–116 (2016). This paper identifies an ATP-competitive small molecule that stabilizes an inactive conformation of KSR2 that is incompatible with heterodimerization with BRAF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Tokarski, J. S. et al. Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain. J. Biol. Chem. 290, 11061–11074 (2015). This study describes a series of ATP-competitive compounds that inhibit TYK2 signalling by binding to the TYK2 JH2 pseudokinase domain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Moslin, R. et al. Identification of imidazo[1,2- b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling. Medchemcomm. 8, 700–712 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Papp, K. et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N. Engl. J. Med. 379,1313–1321 (2018).

    Article  CAS  PubMed  Google Scholar 

  203. Puleo, D. E. et al. Identification and characterization of JAK2 pseudokinase domain small molecule binders. ACS Med. Chem. Lett. 8, 618–621 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Newton, A. S. et al. JAK2 JH2 fluorescence polarization assay and crystal structures for complexes with three small molecules. ACS Med. Chem. Lett. 8, 614–617 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Dong, B. & Silverman, R. H. Alternative function of a protein kinase homology domain in 2’, 5’-oligoadenylate dependent RNase L. Nucleic Acids Res. 27, 439–445 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Jha, B. K. et al. Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity. J. Biol. Chem. 286, 26319–26326 (2011). In this study, activation of RNase L is found to be inhibited by ATP-competitive compounds, including sunitinib and flavonols, such as quercetin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Chen, D. et al. Overexpression of integrin-linked kinase correlates with malignant phenotype in non-small cell lung cancer and promotes lung cancer cell invasion and migration via regulating epithelial-mesenchymal transition (EMT)-related genes. Acta Histochem. 115, 128–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Yan, Z. et al. Overexpression of integrin-linked kinase (ILK) promotes migration and invasion of colorectal cancer cells by inducing epithelial-mesenchymal transition via NF-κB signaling. Acta Histochem. 116, 527–533 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Vaynberg, J. et al. Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion. Nat. Commun. 9, 4465 (2018).

  210. Fukuda, K. et al. Biochemical, proteomic, structural, and thermody 347404 namic characterizations of integrin-linked kinase (ILK): cross-validation of the pseudokinase. J. Biol. Chem. 286, 21886–21895 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Fukuda, K., Gupta, S., Chen, K., Wu, C. & Qin, J. The pseudoactive site of ILK is essential for its binding to α-parvin and localization to focal adhesions. Mol. Cell 36, 819–830 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Fleckenstein, M. C. et al. A Toxoplasma gondii pseudokinase inhibits host IRG resistance proteins. PLOS Biol. 10, e1001358 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Reese, M. L. & Boothroyd, J. C. A conserved non-canonical motif in the pseudoactive site of the ROP5 pseudokinase domain mediates its effect on Toxoplasma virulence. J. Biol. Chem. 286, 29366–29375 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Reese, M. L., Shah, N. & Boothroyd, J. C. The Toxoplasma pseudokinase ROP5 is an allosteric inhibitor of the immunity-related GTPases. J. Biol. Chem. 289, 27849–27858 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Zhang, H. et al. Structure and evolution of the Fam20 kinases. Nat. Comms 9, 1218 (2018).

    Article  CAS  Google Scholar 

  216. Ohren, J. F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192–1197 (2004).

    Article  CAS  PubMed  Google Scholar 

  217. Jia, Y. et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534, 129–132 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Calleja, V., Laguerre, M., Parker, P. J. & Larijani, B. Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition. PLOS Biol. 7, e17 (2009).

    Article  PubMed  CAS  Google Scholar 

  219. Wu, W.-I. et al. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLOS ONE 5, e12913 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Adrián, F. J. et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat. Chem. Biol. 2, 95–102 (2006).

    Article  PubMed  CAS  Google Scholar 

  221. Yang, J. et al. Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site. Chem. Biol. 18, 177–186 (2011).

    Article  CAS  PubMed  Google Scholar 

  222. Zhang, J. et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463, 501–506 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Bono, F. et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell 23, 477–488 (2013).

    Article  CAS  PubMed  Google Scholar 

  224. Herbert, C. et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 23, 489–501 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. Freed, D. M. et al. EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell 171, 683–695 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Moraga, I. et al. Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell 160, 1196–1208 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Engel, M. et al. Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. EMBO J. 25, 5469–5480 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Busschots, K. et al. Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site. Chem. Biol. 19, 1152–1163 (2012).

    Article  CAS  PubMed  Google Scholar 

  229. Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).

    Article  CAS  PubMed  Google Scholar 

  230. Jones, L. H. Small-molecule kinase downregulators. Cell Chem. Biol. 25, 30–35 (2017).

    Article  PubMed  CAS  Google Scholar 

  231. Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  232. Xie, T. et al. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 10, 1006–1012 (2014). This study describes a covalent ATP-competitive small molecule that induces degradation of HER3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Foulkes, D. M. et al. Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. Sci. Signal. 11, eaat7951 (2018). This study reveals that compounds previously identified as covalent inhibitors of EGFR and HER2 can also bind to TRIB2 and induce its degradation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  234. Garrison, J. L., Kunkel, E. J., Hegde, R. S. & Taunton, J. A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum. Nature 436, 285–289 (2005).

    Article  CAS  PubMed  Google Scholar 

  235. Ruiz-Saenz, A. et al. Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. Oncogene 34, 5288–5294 (2015). In this study, an inhibitor of the Sec61 translocon is found to induce HER3 degradation by specifically disrupting the cotranslational insertion of HER3 into the endoplasmic reticulum membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Jacob, W., James, I., Hasmann, M. & Weisser, M. Clinical development of HER3-targeting monoclonal antibodies: Perils and progress. Cancer Treat. Rev. 68, 111–123 (2018).

    Article  CAS  PubMed  Google Scholar 

  237. Im, S.-A. et al. A phase 1 dose-escalation study of anti-HER3 monoclonal antibody LJM716 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast or gastric cancer [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 2519 (2017).

    Google Scholar 

  238. Sequist, L. V. et al. Targeting EGFR and ERBB3 in lung cancer patients: clinical outcomes in a phase I trial of MM-121 in combination with erlotinib [abstract]. J. Clin. Oncol. 30 (Suppl. 15), 7556 (2017).

    Google Scholar 

  239. Sarantopoulos, J. et al. First-in-human phase 1 dose-escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or advanced solid tumors [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 11113 (2017).

    Google Scholar 

  240. Meulendijks, D. et al. A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein [abstract]. J. Clin. Oncol. 31 (Suppl. 15), 2522 (2017).

    Google Scholar 

  241. Wakui, H. et al. Phase 1 and dose-finding study of patritumab (U3-1287), a human monoclonal antibody targeting HER3, in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol. 73, 511–516 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Schoeberl, B. et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 70, 2485–2494 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Mirschberger, C. et al. RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res. 73, 5183–5194 (2013).

    Article  CAS  PubMed  Google Scholar 

  244. Paz-Arez, L. et al. Patritumab plus erlotinib in EGFR wild-type advanced non–small cell lung cancer (NSCLC): part a results of HER3-lung study: topic: EGFR clinical [abstract P3.02b-045]. J. Thorac. Oncol. 12, S1214–S1215 (2017).

    Article  Google Scholar 

  245. Treder, M. et al. Fully human Anti-HER3 monoclonal antibodies (mAbs) inhibit oncogenic signaling and tumor cell growth in vitro and in vivo [abstract]. Cancer Res. 68 (Suppl. 9), LB-20 (2008).

    Google Scholar 

  246. Treder, M. et al. Fully human anti-HER3 mAb U3-1287 (AMG 888) demonstrates unique in vitro and in vivo activities versus other HER family inhibitors in NSCLC models (Poster). EJC Suppl. 6, 99 (2008).

    Article  Google Scholar 

  247. Von Pawel, J. et al. Phase 2 HERALD study of patritumab (P) with erlotinib (E) in advanced NSCLC subjects (SBJs) [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 8045 (2014).

    Article  Google Scholar 

  248. Schaefer, G. et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 20, 472–486 (2011).

    Article  CAS  PubMed  Google Scholar 

  249. Huang, S. et al. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res. 73, 824–833 (2013).

    Article  CAS  PubMed  Google Scholar 

  250. Fayette, J. et al. Randomized phase II study of duligotuzumab (MEHD7945A) versus cetuximab in squamous cell carcinoma of the head and neck (MEHGAN study). Front. Oncol. 6, 232 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Hill, A. G. et al. Phase II study of the dual EGFR/HER3 inhibitor duligotuzumab (MEHD7945A) versus cetuximab in combination with FOLFIRI in RAS wild-type metastatic colorectal cancer. Clin. Cancer Res. 24, 2276–2284 (2018).

    Article  CAS  PubMed  Google Scholar 

  252. Hu, S. et al. Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk. Cancer Res. 75, 159–170 (2015).

    Article  CAS  PubMed  Google Scholar 

  253. Daneshmanesh, A. H. et al. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells. Leukemia 26, 1348–1355 (2012).

    Article  CAS  PubMed  Google Scholar 

  254. Choi, M. Y. et al. Pre-clinical specificity and safety of UC-961, a first-in-class monoclonal antibody targeting ROR1. Clin. Lymphoma Myeloma Leuk. 15, S167–S169 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  255. Nagano, K. et al. Expression of Eph receptor A10 is correlated with lymph node metastasis and stage progression in breast cancer patients. Cancer Med. 2, 972–977 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Nagano, K. et al. Eph receptor A10 has a potential as a target for a prostate cancer therapy. Biochem. Biophys. Res. Commun. 450, 545–549 (2014).

    Article  CAS  PubMed  Google Scholar 

  257. Taki, S. et al. A novel bispecific antibody against human CD3 and ephrin receptor A10 for breast cancer therapy. PLOS ONE 10, e0144712 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  258. Damelin, M. et al. A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci. Transl Med. 9, eaag2611 (2017).

    Article  PubMed  CAS  Google Scholar 

  259. Blaum, B. S. et al. Structure of the pseudokinase domain of BIR2, a regulator of BAK1-mediated immune signaling in Arabidopsis. J. Struct. Biol. 186, 112–121 (2014).

    Article  CAS  PubMed  Google Scholar 

  260. Durzynska, I. et al. STK40 is a pseudokinase that binds the E3 ubiquitin ligase COP1. Structure 25, 287–294 (2016).

    Article  CAS  Google Scholar 

  261. Mayans, O. et al. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 395, 863–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  262. Bogomolovas, J. et al. Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line. Open Biol. 4, 140041 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Mukherjee, K., Sharma, M., Jahn, R., Wahl, M. C. & Südhof, T. C. Evolution of CASK into a Mg2+-sensitive kinase. Sci. Signal. 3, ra33 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Wei, Z. et al. Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures. Mol. Cell 43, 586–598 (2011).

    Article  CAS  PubMed  Google Scholar 

  265. Stefely, J. A. et al. Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis. Mol. Cell 57, 83–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  266. Joubert, S., Jossart, C., McNicoll, N. & De Léan, A. Atrial natriuretic peptide-dependent photolabeling of a regulatory ATP-binding site on the natriuretic peptide receptor-A. FEBS J. 272, 5572–5583 (2005).

    Article  CAS  PubMed  Google Scholar 

  267. Grütter, C. et al. Structural characterization of the RLCK family member BSK8: a pseudokinase with an unprecedented architecture. J. Mol. Biol. 425, 4455–4467 (2013).

    Article  PubMed  CAS  Google Scholar 

  268. Jaleel, M., Saha, S., Shenoy, A. R. & Visweswariah, S. S. The kinase homology domain of receptor guanylyl cyclase C: ATP binding and identification of an adenine nucleotide sensitive site. Biochemistry 45, 1888–1898 (2006).

    Article  CAS  PubMed  Google Scholar 

  269. Kawagoe, T. et al. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat. Immunol. 9, 684–691 (2008).

    Article  CAS  PubMed  Google Scholar 

  270. Toms, A. V. et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat. Struct. Mol. Biol. 20, 1221–1223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Leroy, E. et al. Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix. Biochem. J. 473, 1579–1591 (2016).

    Article  CAS  PubMed  Google Scholar 

  272. Wolf, J. et al. Structural basis for Pan3 binding to Pan2 and its function in mRNA recruitment and deadenylation. EMBO J. 33, 1514–1526 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Christie, M., Boland, A., Huntzinger, E., Weichenrieder, O. & Izaurralde, E. Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Mol. Cell 51, 360–373 (2013).

    Article  CAS  PubMed  Google Scholar 

  274. Schäfer, I. B., Rode, M., Bonneau, F., Schüssler, S. & Conti, E. The structure of the Pan2-Pan3 core complex reveals cross-talk between deadenylase and pseudokinase. Nat. Struct. Mol. Biol. 21, 591–598 (2014).

    Article  PubMed  CAS  Google Scholar 

  275. Jonas, S. et al. An asymmetric PAN3 dimer recruits a single PAN2 exonuclease to mediate mRNA deadenylation and decay. Nat. Struct. Mol. Biol. 21, 599–608 (2014).

    Article  CAS  PubMed  Google Scholar 

  276. Yoshida-Moriguchi, T. et al. SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science 341, 896–899 (2013).

    Article  CAS  PubMed  Google Scholar 

  277. Zhu, Q. et al. Structure of protein O-mannose kinase reveals a unique active site architecture. eLife 5, e22238 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Nagae, M. et al. 3D structural analysis of protein O-mannosyl kinase, POMK, a causative gene product of dystroglycanopathy. Genes Cells 22, 348–359 (2017).

    Article  CAS  PubMed  Google Scholar 

  279. Kamada, H. et al. Generation and characterization of a bispecific diabody targeting both EPH receptor A10 and CD3. Biochem. Biophys. Res. Commun. 456, 908–912 (2015).

    Article  CAS  PubMed  Google Scholar 

  280. Garner, A. P. et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 73, 6024–6035 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Freeman, D., Ogbagabriel, S., Rothe, M., Radinsky, R. & Treder, M. Fully human anti-HER3 monoclonal antibodies (mAbs) have unique in vitro and in vivo functional and antitumor activities versus other HER family inhibitors [abstract]. Cancer Res. 68 (Suppl. 9), LB-21 (2008).

    Google Scholar 

  282. Yonesaka, K., Haratani, K., Hirotani, K. & Nakagawa, K. U3-1402, a novel HER3-targeting ADC, and a novel DNA topoisomerase I inhibitor inhibit the growth of non-small cell lung cancer with EGFR mutation [abstract]. Cancer Res. 77 (Suppl. 13), 44 (2017).

    Google Scholar 

  283. Vincent, S. et al. AV-203, a humanized ERBB3 inhibitory antibody inhibits ligand-dependent and ligand-independent ERBB3 signaling in vitro and in vivo [abstract]. Cancer Res. 72 (Suppl. 8), 2509 (2012).

    Google Scholar 

  284. Alsaid, H. et al. Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice. PLOS ONE 12, e0176075 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  285. Xiao, Z. et al. A potent HER3 monoclonal antibody that blocks both ligand-dependent and -independent activities: differential impacts of PTEN status on tumor response. Mol. Cancer Ther. 15, 689–701 (2016).

    Article  CAS  PubMed  Google Scholar 

  286. Zhang, L. et al. REGN1400, a fully-human ERBB3 antibody, potently inhibits tumor growth in preclinical models, both as a monotherapy and in combination with EGFR or HER2 blockers [abstract]. Cancer Res. 72 (Suppl. 8), 2718 (2012).

    Google Scholar 

  287. Geuijen, C. et al. Mechanism of action of MCLA-128, a humanized bispecific IgG1 antibody targeting the HER2:HER3 heterodimer [abstract]. Cancer Res. 75 (Suppl. 15), LB-261 (2015).

    Google Scholar 

  288. Yu, J. et al. Cirmtuzumab targets ROR1 to inhibit ibrutinib-resistant, Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia. Blood 128, 2034–2034 (2016).

    Google Scholar 

  289. Hudecek, M. et al. The B cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood 116, 4532–4541 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Halford, M. M. et al. A fully human inhibitory monoclonal antibody to the Wnt receptor RYK. PLOS ONE 8, e75447 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors sincerely apologize to all colleagues whose work was omitted in this Review owing to space constraints. N.J. and J.E.K. are supported by a grant from the National Institute of General Medical Sciences to N.J. (R01 GM109176), Susan G. Komen Foundation Training Grant to N.J. (CCR14299947), National Science Foundation Graduate Research Fellowship to J.E.K. and University of California at San Francisco (UCSF) Discovery Fellowship to J.E.K.

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Glossary

Salt bridge

A non-covalent interaction between oppositely charged residues.

Type II inhibitor

An ATP-competitive small molecule that binds to the inactive DFG (Asp-Phe-Gly)-out conformation of a kinase.

Type I inhibitor

An ATP-competitive small molecule that binds to the active DFG (Asp-Phe-Gly)-in conformation of a kinase.

Protomers

Individual subunits of a multimeric protein complex. In the context of a BRAF homodimer, a protomer would be a single BRAF monomer.

Apo

A state of a protein when it has no ligands bound.

Type III inhibitor

A small-molecule kinase inhibitor that binds to an allosteric site adjacent to the ATP-binding pocket and does not interfere with ATP binding.

Type IV inhibitors

Small-molecule kinase inhibitors that bind to allosteric sites distal from the ATP-binding site.

Sec61 translocon

A protein complex that mediates insertion of the transmembrane domains of membrane proteins into the endoplasmic reticulum membrane.

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Kung, J.E., Jura, N. Prospects for pharmacological targeting of pseudokinases. Nat Rev Drug Discov 18, 501–526 (2019). https://doi.org/10.1038/s41573-019-0018-3

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