Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Equivocal, explicit and emergent actions of PKC isoforms in cancer

Abstract

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Domain organization, activation and downregulation pathways for the PKC family.
Fig. 2: Biomarkers of PKC action and inaction.
Fig. 3: Cell cycle controls and PKC.

References

  1. 1.

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

    CAS  PubMed  Google Scholar 

  2. 2.

    Mellor, H. & Parker, P. J. The extended protein kinase C superfamily. Biochem. J. 332, 281–292 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Levin, D. E., Fields, F. O., Kunisawa, R., Bishop, J. M. & Thorner, J. A candidate protein kinase C gene, PKC1, is required for the S. cerevisiae cell cycle. Cell 62, 213–224 (1990).

    CAS  PubMed  Google Scholar 

  4. 4.

    Suh, P. G. et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41, 415–434 (2008).

    CAS  PubMed  Google Scholar 

  5. 5.

    Bunney, T. D. & Katan, M. PLC regulation: emerging pictures for molecular mechanisms. Trends Biochem. Sci. 36, 88–96 (2011).

    CAS  PubMed  Google Scholar 

  6. 6.

    Haga, R. B. & Ridley, A. J. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7, 207–221 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257, 7847–7851 (1982). This paper is the first to define PKC as a target for tumour promoters.

    CAS  PubMed  Google Scholar 

  8. 8.

    Gallegos, L. L. & Newton, A. C. Spatiotemporal dynamics of lipid signaling: protein kinase C as a paradigm. IUBMB Life 60, 782–789 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Tobias, I. S. & Newton, A. C. Protein scaffolds control localized protein kinase Cζ activity. J. Biol. Chem. 291, 13809–13822 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hong, Y. aPKC: the kinase that phosphorylates cell polarity. F1000Res 7, 903 (2018).

    Google Scholar 

  11. 11.

    Amano, M. et al. Identification of a putative target for Rho as the serine–threonine kinase protein kinase N. Science 271, 648–650 (1996).

    CAS  PubMed  Google Scholar 

  12. 12.

    Bauer, A. F. et al. Regulation of protein kinase C-related protein kinase 2 (PRK2) by an intermolecular PRK2–PRK2 interaction mediated by its N-terminal domain. J. Biol. Chem. 287, 20590–20602 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Jaken, S. & Parker, P. J. Protein kinase C binding partners. Bioessays 22, 245–254 (2000).

    CAS  PubMed  Google Scholar 

  14. 14.

    Schechtman, D. & Mochly-Rosen, D. Adaptor proteins in protein kinase C-mediated signal transduction. Oncogene 20, 6339–6347 (2001).

    CAS  PubMed  Google Scholar 

  15. 15.

    Saurin, A. T. et al. The regulated assembly of a PKCε complex controls the completion of cytokinesis. Nat. Cell Biol. 10, 891–901 (2008).

    CAS  PubMed  Google Scholar 

  16. 16.

    Schonwasser, D. C., Marais, R. M., Marshall, C. J. & Parker, P. J. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. Cell Biol. 18, 790–798 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Le Good, J. A. et al. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281, 2042–2045 (1998).

    PubMed  Google Scholar 

  18. 18.

    Chou, M. M. et al. Regulation of protein kinase Cζ by PI3-kinase and PDK-1. Curr. Biol. 8, 1069–1077 (1998).

    CAS  PubMed  Google Scholar 

  19. 19.

    Dutil, E. M., Toker, A. & Newton, A. C. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr. Biol. 8, 1366–1375 (1998).

    CAS  PubMed  Google Scholar 

  20. 20.

    Cameron, A. J., Linch, M. D., Saurin, A. T., Escribano, C. & Parker, P. J. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem. J. 439, 287–297 (2011).

    CAS  PubMed  Google Scholar 

  21. 21.

    Newton, A. C. Protein kinase C as a tumor suppressor. Semin. Cancer Biol. 48, 18–26 (2018).

    CAS  PubMed  Google Scholar 

  22. 22.

    Cameron, A. J., Escribano, C., Saurin, A. T., Kostelecky, B. & Parker, P. J. PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity. Nat. Struct. Mol. Biol. 16, 624–630 (2009). This paper demonstrates that in cells the occupation of the nucleotide binding pocket of PKC with nucleotides or inhibitors has a profound impact on its priming phosphorylation state.

    CAS  PubMed  Google Scholar 

  23. 23.

    Gould, C. M. et al. Active site inhibitors protect protein kinase C from dephosphorylation and stabilize its mature form. J. Biol. Chem. 286, 28922–28930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Srivastava, J., Goris, J., Dilworth, S. M. & Parker, P. J. Dephosphorylation of PKCδ by protein phosphatase 2Ac and its inhibition by nucleotides. FEBS Lett. 516, 265–269 (2002).

    CAS  PubMed  Google Scholar 

  25. 25.

    Torbett, N. E., Casamassima, A. & Parker, P. J. Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1. J. Biol. Chem. 278, 32344–32351 (2003).

    CAS  PubMed  Google Scholar 

  26. 26.

    Newton, A. C. Protein kinase C: poised to signal. Am. J. Physiol. Endocrinol. Metab. 298, E395–E402 (2010).

    CAS  PubMed  Google Scholar 

  27. 27.

    Balendran, A., Hare, G. R., Kieloch, A., Williams, M. R. & Alessi, D. R. Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 484, 217–223 (2000).

    CAS  PubMed  Google Scholar 

  28. 28.

    Cameron, A. J. et al. Protein kinases, from B to C. Biochem. Soc. Trans. 35, 1013–1017 (2007).

    CAS  PubMed  Google Scholar 

  29. 29.

    Nishikawa, K., Toker, A., Johannes, F. J., Songyang, Z. & Cantley, L. C. Determination of the specific substrate sequence motifs of protein kinase C isozymes. J. Biol. Chem. 272, 952–960 (1997).

    CAS  PubMed  Google Scholar 

  30. 30.

    Betson, M. & Settleman, J. A rho-binding protein kinase C-like activity is required for the function of protein kinase N in Drosophila development. Genetics 176, 2201–2212 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lachmann, S. et al. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS ONE 6, e21732 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Carracedo, S., Sacher, F., Brandes, G., Braun, U. & Leitges, M. Redundant role of protein kinase Cδ and epsilon during mouse embryonic development. PLoS ONE 9, e103686 (2014).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Linch, M. et al. A cancer-associated mutation in atypical protein kinase Cι occurs in a substrate-specific recruitment motif. Sci. Signal. 6, ra82 (2013).

    PubMed  Google Scholar 

  34. 34.

    Pears, C. J., Kour, G., House, C., Kemp, B. E. & Parker, P. J. Mutagenesis of the pseudosubstrate site of protein kinase C leads to activation. Eur. J. Biochem. 194, 89–94 (1990).

    CAS  PubMed  Google Scholar 

  35. 35.

    Antal, C. E., Callender, J. A., Kornev, A. P., Taylor, S. S. & Newton, A. C. Intramolecular C2 domain-mediated autoinhibition of protein kinase C βII. Cell Rep. 12, 1252–1260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Stabel, S., Rodriguez-Pena, A., Young, S., Rozengurt, E. & Parker, P. J. Quantitation of protein kinase C by immunoblot—expression in different cell lines and response to phorbol esters. J. Cell Physiol. 130, 111–117 (1987).

    CAS  PubMed  Google Scholar 

  37. 37.

    Lee, H. W., Smith, L., Pettit, G. R. & Smith, J. B. Bryostatin 1 and phorbol ester down-modulate protein kinase C-α and -ε via the ubiquitin/proteasome pathway in human fibroblasts. Mol. Pharmacol. 51, 439–447 (1997).

    CAS  PubMed  Google Scholar 

  38. 38.

    Lee, H. W., Smith, L., Pettit, G. R., Vinitsky, A. & Smith, J. B. Ubiquitination of protein kinase C-α and degradation by the proteasome. J. Biol. Chem. 271, 20973–20976 (1996).

    CAS  PubMed  Google Scholar 

  39. 39.

    Lu, Z. et al. Activation of protein kinase C triggers its ubiquitination and degradation. Mol. Cell Biol. 18, 839–845 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Hansra, G. et al. Multisite dephosphorylation and desensitization of conventional protein kinase C isotypes. Biochem. J. 342, 337–344 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Prevostel, C., Alice, V., Joubert, D. & Parker, P. J. Protein kinase Cα actively downregulates through caveolae-dependent traffic to an endosomal compartment. J. Cell Sci. 113, 2575–2584 (2000).

    CAS  PubMed  Google Scholar 

  42. 42.

    Leontieva, O. V. & Black, J. D. Identification of two distinct pathways of protein kinase Cα down-regulation in intestinal epithelial cells. J. Biol. Chem. 279, 5788–5801 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Lum, M. A., Pundt, K. E., Paluch, B. E., Black, A. R. & Black, J. D. Agonist-induced down-regulation of endogenous protein kinase Cα through an endolysosomal mechanism. J. Biol. Chem. 288, 13093–13109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Melnikov, S. & Sagi-Eisenberg, R. Down-regulating protein kinase Cα: functional cooperation between the proteasome and the endocytic system. Cell Signal. 21, 1607–1619 (2009).

    CAS  PubMed  Google Scholar 

  45. 45.

    Chen, D. et al. Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase. J. Biol. Chem. 282, 33776–33787 (2007).

    CAS  PubMed  Google Scholar 

  46. 46.

    Min, X., Zhang, X., Sun, N., Acharya, S. & Kim, K. M. Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity. Biochem. Pharmacol. 170, 113675 (2019).

    CAS  PubMed  Google Scholar 

  47. 47.

    Nakamura, M., Tokunaga, F., Sakata, S. & Iwai, K. Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex. Biochem. Biophys. Res. Commun. 351, 340–347 (2006).

    CAS  PubMed  Google Scholar 

  48. 48.

    Baffi, T. R., Van, A. N., Zhao, W., Mills, G. B. & Newton, A. C. Protein kinase C quality control by phosphatase PHLPP1 unveils loss-of-function mechanism in cancer. Mol. Cell 74, 378–392.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Abrahamsen, H. et al. Peptidyl-prolyl isomerase Pin1 controls down-regulation of conventional protein kinase C isozymes. J. Biol. Chem. 287, 13262–13278 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Perander, M., Bjorkoy, G. & Johansen, T. Nuclear import and export signals enable rapid nucleocytoplasmic shuttling of the atypical protein kinase Cλ. J. Biol. Chem. 276, 13015–13024 (2001).

    CAS  PubMed  Google Scholar 

  51. 51.

    Ivaska, J., Bosca, L. & Parker, P. J. PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1. Nat. Cell Biol. 5, 363–369 (2003).

    CAS  PubMed  Google Scholar 

  52. 52.

    Pelech, S. L., Meier, K. E. & Krebs, E. G. Rapid microassay for protein kinase C translocation in Swiss 3T3 cells. Biochemistry 25, 8348–8353 (1986).

    CAS  PubMed  Google Scholar 

  53. 53.

    Sakai, N. et al. Direct visualization of the translocation of the γ-subspecies of protein kinase C in living cells using fusion proteins with green fluorescent protein. J. Cell Biol. 139, 1465–1476 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Gao, X. et al. Single cell analysis of PKC activation during proliferation and apoptosis induced by laser irradiation. J. Cell Physiol. 206, 441–448 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Flint, A. J., Paladini, R. D. & Koshland, D. E. Jr. Autophosphorylation of protein kinase C at three separated regions of its primary sequence. Science 249, 408–411 (1990).

    CAS  PubMed  Google Scholar 

  56. 56.

    Ng, T. et al. Imaging protein kinase Cα activation in cells. Science 283, 2085–2089 (1999).

    CAS  PubMed  Google Scholar 

  57. 57.

    Durgan, J. et al. The identification and characterization of novel PKCε phosphorylation sites provide evidence for functional cross-talk within the PKC superfamily. Biochem. J. 411, 319–331 (2008).

    CAS  PubMed  Google Scholar 

  58. 58.

    Durgan, J., Michael, N., Totty, N. & Parker, P. J. Novel phosphorylation site markers of protein kinase Cδ activation. FEBS Lett. 581, 3377–3381 (2007).

    CAS  PubMed  Google Scholar 

  59. 59.

    Rodriguez, J. et al. aPKC cycles between functionally distinct PAR protein assemblies to drive cell polarity. Dev. Cell 42, 400–415.e9 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Wodarz, A. & Näthke, I. Cell polarity in development and cancer. Nat. Cell Biol. 9, 1016–1024 (2007).

    CAS  PubMed  Google Scholar 

  61. 61.

    Linch, M. et al. Regulation of polarized morphogenesis by protein kinase Cι in oncogenic epithelial spheroids. Carcinogenesis 35, 396–406 (2014).

    CAS  PubMed  Google Scholar 

  62. 62.

    Slaga, T. J. Overview of tumor promotion in animals. Env. Health Perspect. 50, 3–14 (1983).

    CAS  Google Scholar 

  63. 63.

    Hecker, E. Three stage carcinogenesis in mouse skin — recent results and present status of an advanced model system of chemical carcinogenesis. Toxicol. Pathol. 15, 245–258 (1987).

    CAS  PubMed  Google Scholar 

  64. 64.

    Balmain, A. Transforming ras oncogenes and multistage carcinogenesis. Br. J. Cancer 51, 1–7 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Fujiki, H., Sueoka, E. & Suganuma, M. Tumor promoters: from chemicals to inflammatory proteins. J. Cancer Res. Clin. Oncol. 139, 1603–1614 (2013).

    CAS  PubMed  Google Scholar 

  66. 66.

    Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308, 693–698 (1984).

    CAS  PubMed  Google Scholar 

  67. 67.

    Ono, Y. et al. Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence. Proc. Natl Acad. Sci. USA 86, 4868–4871 (1989). This paper is the first demonstration that the cysteine-rich C1 domains are bound by phorbol esters, impacting our definition of this entire class of responsive proteins.

    CAS  PubMed  Google Scholar 

  68. 68.

    Fujiki, H. et al. Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin. Biochem. Biophys. Res. Commun. 120, 339–343 (1984).

    CAS  PubMed  Google Scholar 

  69. 69.

    Miyake, R. et al. Activation of protein kinase C by non-phorbol tumor promoter, mezerein. Biochem. Biophys. Res. Commun. 121, 649–656 (1984).

    CAS  PubMed  Google Scholar 

  70. 70.

    Arcoleo, J. P. & Weinstein, I. B. Activation of protein kinase C by tumor promoting phorbol esters, teleocidin and aplysiatoxin in the absence of added calcium. Carcinogenesis 6, 213–217 (1985).

    CAS  PubMed  Google Scholar 

  71. 71.

    Thastrup, O., Cullen, P. J., Drobak, B. K., Hanley, M. R. & Dawson, A. P. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc. Natl Acad. Sci. USA 87, 2466–2470 (1990).

    CAS  PubMed  Google Scholar 

  72. 72.

    Haystead, T. A. et al. Effects of the tumour promoter okadaic acid on intracellular protein phosphorylation and metabolism. Nature 337, 78–81 (1989).

    CAS  PubMed  Google Scholar 

  73. 73.

    Manzow, S., Richter, K. H., Stempka, L., Fürstenberger, G. & Marks, F. Evidence against a role of general protein kinase C downregulation in skin tumor promotion. Int. J. Cancer 85, 503–507 (2000).

    CAS  PubMed  Google Scholar 

  74. 74.

    Arnott, C. H. et al. Tumour necrosis factor-α mediates tumour promotion via a PKCα- and AP-1-dependent pathway. Oncogene 21, 4728–4738 (2002).

    CAS  PubMed  Google Scholar 

  75. 75.

    Kazanietz, M. G. Novel “nonkinase” phorbol ester receptors: the C1 domain connection. Mol. Pharmacol. 61, 759–767 (2002).

    CAS  PubMed  Google Scholar 

  76. 76.

    Soloff, R. S., Katayama, C., Lin, M. Y., Feramisco, J. R. & Hedrick, S. M. Targeted deletion of protein kinase Cλ reveals a distribution of functions between the two atypical protein kinase C isoforms. J. Immunol. 173, 3250–3260 (2004).

    CAS  PubMed  Google Scholar 

  77. 77.

    Quetier, I. et al. Knockout of the PKN family of rho effector kinases reveals a non-redundant role for PKN2 in developmental mesoderm expansion. Cell Rep. 14, 440–448 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Oster, H. & Leitges, M. Protein kinase Cα but not PKCζ suppresses intestinal tumor formation in ApcMin/+ mice. Cancer Res. 66, 6955–6963 (2006). This paper presents direct evidence that, in the ApcMin/+ mouse model of colorectal cancer, PKCα suppresses tumour progression.

    CAS  PubMed  Google Scholar 

  79. 79.

    Cataisson, C. et al. Activation of cutaneous protein kinase Cα induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J. Immunol. 171, 2703–2713 (2003).

    CAS  PubMed  Google Scholar 

  80. 80.

    Wang, H. Q. & Smart, R. C. Overexpression of protein kinase C-α in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-α expression but not tumor promotion. J. Cell Sci. 112, 3497–3506 (1999).

    CAS  PubMed  Google Scholar 

  81. 81.

    Hara, T. et al. Deficiency of protein kinase Cα in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis. Cancer Res. 65, 7356–7362 (2005).

    CAS  PubMed  Google Scholar 

  82. 82.

    Reddig, P. J. et al. Transgenic mice overexpressing protein kinase Cδ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 59, 5710–5718 (1999).

    CAS  PubMed  Google Scholar 

  83. 83.

    Aziz, M. H., Wheeler, D. L., Bhamb, B. & Verma, A. K. Protein kinase Cδ overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: a possible link to specific cytokines and cyclooxygenase-2. Cancer Res. 66, 713–722 (2006).

    CAS  PubMed  Google Scholar 

  84. 84.

    Miyamoto, A. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–869 (2002). This paper presents a description of B cell lymphoproliferative disorder in the PKCδ knockout mouse.

    CAS  PubMed  Google Scholar 

  85. 85.

    Mecklenbrauker, I., Saijo, K., Zheng, N. Y., Leitges, M. & Tarakhovsky, A. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416, 860–865 (2002).

    PubMed  Google Scholar 

  86. 86.

    Kuehn, H. S. et al. Loss-of-function of the protein kinase Cδ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood 121, 3117–3125 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Allen-Petersen, B. L., Carter, C. J., Ohm, A. M. & Reyland, M. E. Protein kinase Cδ is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer. Oncogene 33, 1306–1315 (2014).

    CAS  PubMed  Google Scholar 

  88. 88.

    Symonds, J. M. et al. Protein kinase Cδ is a downstream effector of oncogenic K-ras in lung tumors. Cancer Res. 71, 2087–2097 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Leitges, M. et al. Immunodeficiency in protein kinase Cβ-deficient mice. Science 273, 788–791 (1996).

    CAS  PubMed  Google Scholar 

  90. 90.

    Tsui, C. et al. Protein kinase C-β dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis. Immunity 48, 1144–1159.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Pfeifhofer, C. et al. Defective IgG2a/2b class switching in PKCα–/– mice. J. Immunol. 176, 6004–6011 (2006).

    CAS  PubMed  Google Scholar 

  92. 92.

    Martini, S. et al. PKCε promotes human TH17 differentiation: implications in the pathophysiology of psoriasis. Eur. J. Immunol. 48, 644–654 (2018).

    CAS  PubMed  Google Scholar 

  93. 93.

    Castrillo, A. et al. Protein kinase Cε is required for macrophage activation and defense against bacterial infection. J. Exp. Med. 194, 1231–1242 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Pfeifhofer, C. et al. Protein kinase Cθ affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197, 1525–1535 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Thuille, N. et al. Loss-of-function phenotype of a PKCθT219A knockin mouse strain. Cell Commun. Signal. 17, 141 (2019).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    He, X. et al. Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J. Invest. Dermatol. 134, 975–983 (2014).

    CAS  PubMed  Google Scholar 

  97. 97.

    Kwon, M. J., Ma, J., Ding, Y., Wang, R. & Sun, Z. Protein kinase C-θ promotes TH17 differentiation via upregulation of Stat3. J. Immunol. 188, 5887–5897 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kong, K. F. et al. Protein kinase C-η controls CTLA-4-mediated regulatory T cell function. Nat. Immunol. 15, 465–472 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Chida, K. et al. Disruption of protein kinase Cη results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res. 63, 2404–2408 (2003).

    CAS  PubMed  Google Scholar 

  100. 100.

    Park, D. W. et al. TLR2 stimulates ABCA1 expression via PKC-η and PLD2 pathway. Biochem. Biophys. Res. Commun. 430, 933–937 (2013).

    CAS  PubMed  Google Scholar 

  101. 101.

    Fu, G. et al. Protein kinase Cη is required for T cell activation and homeostatic proliferation. Sci. Signal. 4, ra84 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Wallace, J. A. et al. Protein kinase Cβ in the tumor microenvironment promotes mammary tumorigenesis. Front. Oncol. 4, 87 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Park, E. et al. Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aax9340 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Mukai, H. et al. PKN3 is the major regulator of angiogenesis and tumor metastasis in mice. Sci. Rep. 6, 18979 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Hattori, Y., Kikuchi, T., Nakamura, M., Ozaki, K. I. & Onishi, H. Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases. Oncol. Lett. 14, 5157–5166 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Leenders, F. et al. PKN3 is required for malignant prostate cell growth downstream of activated PI3-kinase. EMBO J. 23, 3303–3313 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Kraft, A. S., Smith, J. B. & Berkow, R. L. Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl Acad. Sci. USA 83, 1334–1338 (1986).

    CAS  PubMed  Google Scholar 

  108. 108.

    Mackanos, E. A., Pettit, G. R. & Ramsdell, J. S. Bryostatins selectively regulate protein kinase C-mediated effects on GH4 cell proliferation. J. Biol. Chem. 266, 11205–11212 (1991).

    CAS  PubMed  Google Scholar 

  109. 109.

    Szallasi, Z., Smith, C. B., Pettit, G. R. & Blumberg, P. M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J. Biol. Chem. 269, 2118–2124 (1994).

    CAS  PubMed  Google Scholar 

  110. 110.

    Hennings, H. et al. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8, 1343–1346 (1987). This paper demonstrates that despite its shared ability to activate PKC, bryostatin 1 inhibits phorbol ester-promoted tumour formation.

    CAS  PubMed  Google Scholar 

  111. 111.

    Boyle, G. M. et al. Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. PLoS ONE 9, e108887 (2014). This paper presents evidence that the PKC-activating epoxytigliane EBC-46 can trigger tumour regression on intratumoural injection.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Miller, J. et al. Dose characterization of the investigational anticancer drug tigilanol tiglate (EBC-46) in the local treatment of canine mast cell tumors. Front. Vet. Sci. 6, 106 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    CAS  PubMed  Google Scholar 

  114. 114.

    Antal, C. E. et al. Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell 160, 489–502 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Bangham, C. R. & Ratner, L. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? Curr. Opin. Virol. 14, 93–100 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Kataoka, K. et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 47, 1304–1315 (2015). This paper presents a comprehensive description of the mutational landscape of ATLL and the identification of PKCβ as a frequent mutation target.

    CAS  PubMed  Google Scholar 

  117. 117.

    Wang, C., Shang, Y., Yu, J. & Zhang, M. Substrate recognition mechanism of atypical protein kinase Cs revealed by the structure of PKCι in complex with a substrate peptide from Par-3. Structure 20, 791–801 (2012).

    CAS  PubMed  Google Scholar 

  118. 118.

    Shinohara, H. et al. PKCβ regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J. Exp. Med. 202, 1423–1431 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Soriano, E. V. et al. aPKC inhibition by Par3 CR3 flanking regions controls substrate access and underpins apical-junctional polarization. Dev. Cell 38, 384–398 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Linch, M. Protein Kinase Cι in Mammalian Cell Polarity and Cancer. PhD thesis, Univ. College London (2012).

  121. 121.

    Shimoyama, M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br. J. Haematol. 79, 428–437 (1991).

    CAS  PubMed  Google Scholar 

  122. 122.

    Brat, D. J. et al. Third ventricular chordoid glioma: a distinct clinicopathologic entity. J. Neuropathol. Exp. Neurol. 57, 283–290 (1998).

    CAS  PubMed  Google Scholar 

  123. 123.

    Morais, B. A., Menendez, D. F., Medeiros, R. S., Teixeira, M. J. & Lepski, G. A. Chordoid glioma: case report and review of the literature. Int. J. Surg. Case Rep. 7c, 168–171 (2015).

    PubMed  Google Scholar 

  124. 124.

    Rosenberg, S. et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat. Commun. 9, 2371 (2018).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Goode, B. et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat. Commun. 9, 810 (2018). Together with Rosenberg et al. (2018), this paper demonstrates a fully penetrant mutation in PKCα in chordoid gliomas.

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Madhusudan et al. cAMP-dependent protein kinase: crystallographic insights into substrate recognition and phosphotransfer. Protein Sci. 3, 176–187 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Leitges, M. et al. Knockout of PKCα enhances insulin signaling through PI3K. Mol. Endocrinol. 16, 847–858 (2002).

    PubMed  Google Scholar 

  128. 128.

    Cameron, A. J., Procyk, K. J., Leitges, M. & Parker, P. J. PKCα protein but not kinase activity is critical for glioma cell proliferation and survival. Int. J. Cancer 123, 769–779 (2008).

    CAS  PubMed  Google Scholar 

  129. 129.

    Black, A. R. & Black, J. D. Protein kinase C signaling and cell cycle regulation. Front. Immunol. 3, 423 (2012).

    PubMed  Google Scholar 

  130. 130.

    Poli, A., Mongiorgi, S., Cocco, L. & Follo, M. Y. Protein kinase C involvement in cell cycle modulation. Biochem. Soc. Trans. 42, 1471–1476 (2014).

    CAS  PubMed  Google Scholar 

  131. 131.

    Gao, Q. et al. PKCα affects cell cycle progression and proliferation in human RPE cells through the downregulation of p27kip1. Mol. Vis. 15, 2683–2695 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Kashiwagi, M. et al. PKCη associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes. Oncogene 19, 6334–6341 (2000).

    CAS  PubMed  Google Scholar 

  133. 133.

    Mall, M. et al. Mitotic lamin disassembly is triggered by lipid-mediated signaling. J. Cell Biol. 198, 981–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Edens, L. J., Dilsaver, M. R. & Levy, D. L. PKC-mediated phosphorylation of nuclear lamins at a single serine residue regulates interphase nuclear size in Xenopus and mammalian cells. Mol. Biol. Cell 28, 1389–1399 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Goss, V. L. et al. Identification of nuclear βII protein kinase C as a mitotic lamin kinase. J. Biol. Chem. 269, 19074–19080 (1994).

    CAS  PubMed  Google Scholar 

  136. 136.

    Larijani, B. et al. Principle of duality in phospholipids: regulators of membrane morphology and dynamics. Biochem. Soc. Trans. 42, 1335–1342 (2014).

    CAS  PubMed  Google Scholar 

  137. 137.

    Brownlow, N., Pike, T., Zicha, D., Collinson, L. & Parker, P. J. Mitotic catenation is monitored and resolved by a PKCε-regulated pathway. Nat. Commun. 5, 5685 (2014). This paper defines, for the first time, the cell cycle dependence on PKCε in cells with a dysfunctional Topo2-dependent G2 arrest.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Downes, C. S. et al. A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature 372, 467–470 (1994).

    CAS  PubMed  Google Scholar 

  139. 139.

    Pandey, N. et al. Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases. J. Cell Biol. https://doi.org/10.1083/jcb.201807189 (2019).

    Article  PubMed Central  Google Scholar 

  140. 140.

    Deiss, K. et al. A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest. Nucleic Acids Res. 47, 2906–2921 (2019). This paper demonstrates that a genome-wide screen for genes engaged in the Topo2-dependent G2 arrest provides molecular insight into the context of PKCε dependence.

    CAS  PubMed  Google Scholar 

  141. 141.

    Martini, S. et al. PKCε controls mitotic progression by regulating centrosome migration and mitotic spindle assembly. Mol. Cancer Res. 16, 3–15 (2018).

    CAS  PubMed  Google Scholar 

  142. 142.

    Kelly, J. R. et al. The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition. Nat. Commun. 11, 1396 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Pike, T., Brownlow, N., Kjaer, S., Carlton, J. & Parker, P. J. PKCε switches Aurora B specificity to exit the abscission checkpoint. Nat. Commun. 7, 13853 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Chen, D., Purohit, A., Halilovic, E., Doxsey, S. J. & Newton, A. C. Centrosomal anchoring of protein kinase C βII by pericentrin controls microtubule organization, spindle function, and cytokinesis. J. Biol. Chem. 279, 4829–4839 (2004).

    CAS  PubMed  Google Scholar 

  145. 145.

    Kawamoto, S. & Hidaka, H. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets. Biochem. Biophys. Res. Commun. 125, 258–264 (1984).

    CAS  PubMed  Google Scholar 

  146. 146.

    Tamaoki, T. et al. Staurosporine, a potent inhibitor of phospholipid/Ca++ dependent protein kinase. Biochem. Biophys. Res. Commun. 135, 397–402 (1986).

    CAS  PubMed  Google Scholar 

  147. 147.

    Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–15781 (1991).

    CAS  PubMed  Google Scholar 

  148. 148.

    Mackay, H. J. & Twelves, C. J. Targeting the protein kinase C family: are we there yet? Nat. Rev. Cancer 7, 554–562 (2007).

    CAS  PubMed  Google Scholar 

  149. 149.

    Roffey, J. et al. Protein kinase C intervention: the state of play. Curr. Opin. Cell Biol. 21, 268–279 (2009).

    CAS  PubMed  Google Scholar 

  150. 150.

    Wang, H. B., Wang, X. Y., Liu, L. P., Qin, G. W. & Kang, T. G. Tigliane diterpenoids from the Euphorbiaceae and Thymelaeaceae families. Chem. Rev. 115, 2975–3011 (2015).

    CAS  PubMed  Google Scholar 

  151. 151.

    Raghuvanshi, R. & Bharate, S. B. Preclinical and clinical studies on bryostatins, a class of marine-derived protein kinase C modulators: a mini-review. Curr. Top. Med. Chem. 20, 1124–1135 (2020).

    CAS  PubMed  Google Scholar 

  152. 152.

    Saavedra, A. et al. Chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells in a PKC-independent manner. Biochim. Biophys. Acta Gen. Subj. 1861, 922–935 (2017).

    CAS  PubMed  Google Scholar 

  153. 153.

    Dar, M. I. et al. Rottlerin is a pan phosphodiesterase inhibitor and can induce neurodifferentiation in IMR-32 human neuroblastoma cells. Eur. J. Pharmacol. 857, 172448 (2019).

    CAS  PubMed  Google Scholar 

  154. 154.

    Meyer, T. et al. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int. J. Cancer 43, 851–856 (1989).

    CAS  PubMed  Google Scholar 

  155. 155.

    Kayser, S., Levis, M. J. & Schlenk, R. F. Midostaurin treatment in FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Expert. Rev. Clin. Pharmacol. 10, 1177–1189 (2017).

    CAS  PubMed  Google Scholar 

  156. 156.

    Graves, P. R. et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600–5605 (2000).

    CAS  PubMed  Google Scholar 

  157. 157.

    Bourhill, T., Narendran, A. & Johnston, R. N. Enzastaurin: a lesson in drug development. Crit. Rev. Oncol. Hematol. 112, 72–79 (2017).

    CAS  PubMed  Google Scholar 

  158. 158.

    Carducci, M. A. et al. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase Cβ inhibitor, in patients with advanced cancer. J. Clin. Oncol. 24, 4092–4099 (2006).

    CAS  PubMed  Google Scholar 

  159. 159.

    Clamp, A. & Jayson, G. C. The clinical development of the bryostatins. Anticancer Drugs 13, 673–683 (2002).

    CAS  PubMed  Google Scholar 

  160. 160.

    Ku, G. Y. et al. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol. 62, 875–880 (2008).

    CAS  PubMed  Google Scholar 

  161. 161.

    Panizza, B. J. et al. Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46). EBioMedicine 50, 433–441 (2019).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Decatur, C. L. et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 134, 728–733 (2016).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Gresset, A., Sondek, J. & Harden, T. K. The phospholipase C isozymes and their regulation. Subcell. Biochem. 58, 61–94 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02273219?term=aeb071&draw=2&rank=1 (2018).

  165. 165.

    Skvara, H. et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J. Clin. Invest. 118, 3151–3159 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Piperno-Neumann, S. et al. Genomic profiling of metastatic uveal melanoma and clinical results of a phase I study of the protein kinase C inhibitor AEB071. Mol. Cancer Ther. https://doi.org/10.1158/1535-7163.Mct-19-0098 (2020).

    Article  PubMed  Google Scholar 

  167. 167.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03947385 (2020).

  168. 168.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02601378 (2020).

  169. 169.

    Kapiteijn, E. et al. Abstract CT068: a phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma. Cancer Res. 79, CT068–CT068 (2019).

    Google Scholar 

  170. 170.

    Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 25, 1741–1746 (2007).

    CAS  PubMed  Google Scholar 

  171. 171.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03263026 (2020).

  172. 172.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03492125 (2019).

  173. 173.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01737502 (2020).

  174. 174.

    Erdogan, E. et al. Aurothiomalate inhibits transformed growth by targeting the PB1 domain of protein kinase Cι. J. Biol. Chem. 281, 28450–28459 (2006).

    CAS  PubMed  Google Scholar 

  175. 175.

    Suzuki, A. & Ohno, S. The PAR–aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).

    CAS  PubMed  Google Scholar 

  176. 176.

    Drummond, M. L. & Prehoda, K. E. Molecular control of atypical protein kinase C: tipping the balance between self-renewal and differentiation. J. Mol. Biol. 428, 1455–1464 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Etienne-Manneville, S. From signaling pathways to microtubule dynamics: the key players. Curr. Opin. Cell Biol. 22, 104–111 (2010).

    CAS  PubMed  Google Scholar 

  178. 178.

    Murray, N. R. & Fields, A. P. Atypical protein kinase Cι protects human leukemia cells against drug-induced apoptosis. J. Biol. Chem. 272, 27521–27524 (1997).

    CAS  PubMed  Google Scholar 

  179. 179.

    Weichert, W., Gekeler, V., Denkert, C., Dietel, M. & Hauptmann, S. Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int. J. Oncol. 23, 633–639 (2003).

    CAS  PubMed  Google Scholar 

  180. 180.

    Zhang, L. et al. Integrative genomic analysis of protein kinase C (PKC) family identifies PKCι as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 66, 4627–4635 (2006).

    CAS  PubMed  Google Scholar 

  181. 181.

    Eder, A. M. et al. Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 12519–12524 (2005).

    CAS  PubMed  Google Scholar 

  182. 182.

    Regala, R. P. et al. Atypical protein kinase Cι is an oncogene in human non-small cell lung cancer. Cancer Res. 65, 8905–8911 (2005).

    CAS  PubMed  Google Scholar 

  183. 183.

    Li, Q. et al. Correlation of aPKC-ι and E-cadherin expression with invasion and prognosis of cholangiocarcinoma. Hepatob. Pancreat. Dis. Int. 7, 70–75 (2008).

    Google Scholar 

  184. 184.

    Yang, Y. L. et al. Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosomes Cancer 47, 127–136 (2008).

    CAS  PubMed  Google Scholar 

  185. 185.

    Scotti, M. L., Bamlet, W. R., Smyrk, T. C., Fields, A. P. & Murray, N. R. Protein kinase Cι is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 70, 2064–2074 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Ishiguro, H. et al. aPKCλ/ι promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6. Proc. Natl Acad. Sci. USA 106, 16369–16374 (2009).

    CAS  PubMed  Google Scholar 

  187. 187.

    Ma, L. et al. Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis. Cell 152, 599–611 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Reina-Campos, M., Diaz-Meco, M. T. & Moscat, J. The dual roles of the atypical protein kinase Cs in cancer. Cancer Cell 36, 218–235 (2019). This paper presents a detailed commentary on aPKC in cancer models.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Reina-Campos, M. et al. Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell 35, 385–400.e9 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Nakanishi, Y. et al. Simultaneous loss of both atypical protein kinase C genes in the intestinal epithelium drives serrated intestinal cancer by impairing immunosurveillance. Immunity 49, 1132–1147.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Huang, X. et al. An atypical protein kinase C (PKCζ) plays a critical role in lipopolysaccharide-activated NF-κB in human peripheral blood monocytes and macrophages. J. Immunol. 182, 5810–5815 (2009).

    CAS  PubMed  Google Scholar 

  192. 192.

    Murray, N. R. et al. Protein kinase Cι is required for Ras transformation and colon carcinogenesis in vivo. J. Cell Biol. 164, 797–802 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Regala, R. P. et al. Atypical protein kinase Cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis. Cancer Res. 69, 7603–7611 (2009). This paper demonstrates that knockout of PKCι suppresses lung tumour formation at switch on of G12D-mutant K-Ras expression.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank A. Fields and M. Reyland for commenting on the manuscript. They also acknowledge support from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001130), the UK Medical Research Council (FC001130) and the Wellcome Trust (FC001130). M.L. is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre (no grant numbers apply).

Author information

Affiliations

Authors

Contributions

P.J.P. contributed to all aspects of the article. V.C., M.L. and P.C. contributed to researching data for the article and reviewing and/or editing the manuscript before submission. S.J.B., M.C., J.J.T.M., S.M., N.Q.M., T.S. and L.W. contributed to writing the article and reviewing and/or editing it before submission.

Corresponding author

Correspondence to Peter J. Parker.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks M.G. Kazanietz, M. Leitges and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

cBioPortal: https://www.cbioportal.org

FDA orphan status was designated to bryostatin: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm

PKC412 in acute myeloid leukaemia: https://clinicaltrials.gov/ct2/results?cond = AML&term = PKC412

PKC412 in myelodysplastic syndrome: https://clinicaltrials.gov/ct2/results?cond = MDS&term = PKC412

Tigilanol tiglate: https://www.ema.europa.eu/en/medicines/veterinary/EPAR/stelfonta

Supplementary information

Glossary

1,2-diacylglycerol

(DAG). A neutral lipid component of membranes, serving in the biosynthesis of more complex lipids and as a signalling lipid.

Conformer

Used in a generic manner to indicate a particular protein conformation.

MMTV-ERBB2 transformation model

A transgenic mouse model with expression of the receptor tyrosine kinase ERBB2 under the control of the mammary gland selective MMTV promoter.

Bryostatins

Trace bioactive cyclic polyketides first identified in marine bryozoan Bugula neritina; they likely originate from the symbiont B. neritina.

Epoxytiglianes

Bioactive compounds originally identified in the kernels of Fontainea picrosperma fruits and related to phorbol esters (tigliane family of diterpenes).

Private mutations

Those rare mutations that appear only once in cancer genomes, that is, are private to that patient.

Topoisomerase 2α

(Topo2α). One of two genes in mammals that catalyse the resolution of intertwined, catenated DNA, through double-strand cutting, strand passage and religation reactions.

Borealin

One of the components of the chromosome passenger complex (CPC), alongside INCENP and survivin, regulating the localization and activity of the co-associated Aurora B, which completes the CPC.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Parker, P.J., Brown, S.J., Calleja, V. et al. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer 21, 51–63 (2021). https://doi.org/10.1038/s41568-020-00310-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing