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Controlling the master—upstream regulation of the tumor suppressor LKB1

Abstract

The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer. LKB1 activates several downstream kinases of the AMPK family by direct phosphorylation in the T-loop. In particular the activation of AMPK upon energetic stress has been intensively analyzed in various diseases, including cancer to induce a metabolic switch from anabolism towards catabolism to regulate energy homeostasis and cell survival. In contrast, the regulation of LKB1 itself has long been only poorly understood. Only in the last years, several proteins and posttranslational modifications of LKB1 have been analyzed to control its localization, activity and recognition of substrates. Here, we summarize the current knowledge about the upstream regulation of LKB1, which is important for the understanding of the pathogenesis of many types of tumors.

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References

  1. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391:184–7.

    Article  CAS  PubMed  Google Scholar 

  2. Jansen M, Klooster JPten, Offerhaus GJ, Clevers H. LKB1 and AMPK family signaling. Intim Link Cell polarity Energy Metab Physiol Rev. 2009;89:777–98.

    CAS  Google Scholar 

  3. Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet. 1998;63:1641–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15.

    Article  CAS  PubMed  Google Scholar 

  5. Miyoshi H, Nakau M, Ishikawa T-o, Seldin MF, Oshima M, Taketo MM. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 2002;62:2261–6.

    CAS  PubMed  Google Scholar 

  6. Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature. 2002;419:162–7.

    Article  CAS  PubMed  Google Scholar 

  7. Jishage K-i, Nezu J-i, Kawase Y, Iwata T, Watanabe M, Miyoshi A, et al. Role of Lkb1, the causative gene of Peutz-Jegher’s syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci USA. 2002;99:8903–8.

    Article  CAS  PubMed  Google Scholar 

  8. Rossi DJ, Ylikorkala A, Korsisaari N, Salovaara R, Luukko K, Launonen V, et al. Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc Natl Acad Sci USA. 2002;99:12327–32.

    Article  CAS  PubMed  Google Scholar 

  9. Wei C, Amos CI, Stephens LC, Campos I, Deng JM, Behringer RR, et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res. 2005;65:11297–303.

    Article  CAS  PubMed  Google Scholar 

  10. McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol. 2000;95:596–604.

    Article  CAS  PubMed  Google Scholar 

  11. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62:3659–62.

    CAS  PubMed  Google Scholar 

  12. Matsumoto S, Iwakawa R, Takahashi K, Kohno T, Nakanishi Y, Matsuno Y, et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene. 2007;26:5911–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gill RK, Yang S-H, Meerzaman D, Mechanic LE, Bowman ED, Jeon H-S, et al. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene. 2011;30:3784–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M. Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene. 2004;23:4037–40.

    Article  CAS  PubMed  Google Scholar 

  15. Wingo SN, Gallardo TD, Akbay EA, Liang M-C, Contreras CM, Boren T, et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE. 2009;4:e5137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Tanwar PS, Mohapatra G, Chiang S, Engler DA, Zhang L, Kaneko-Tarui T, et al. Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. Carcinogenesis. 2014;35:546–53.

    Article  CAS  PubMed  Google Scholar 

  17. George SHL, Milea A, Sowamber R, Chehade R, Tone A, Shaw PA. Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis. Oncogene. 2015;35:59–68.

    Article  PubMed  CAS  Google Scholar 

  18. Morton JP, Jamieson NB, Karim SA, Athineos D, Ridgway RA, Nixon C, et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology. 2010;139:586–97. 597.e1-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Oncogene. 1999;18:1777–80.

    Article  CAS  PubMed  Google Scholar 

  20. Rowan A, Bataille V, MacKie R, Healy E, Bicknell D, Bodmer W, et al. Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanomas. J Invest Dermatol. 1999;112:509–11.

    Article  CAS  PubMed  Google Scholar 

  21. Dogliotti G, Kullmann L, Dhumale P, Thiele C, Panichkina O, Mendl G, et al. Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression. Nat Commun. 2017;8:15747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cidlinsky N, Dogliotti G, Pukrop T, Jung R, Weber F, Krahn MP. Inactivation of the LKB1-AMPK signaling pathway does not contribute to salivary gland tumor development—a short report. Cell Oncol. 2016;39:389–96.

    Article  CAS  Google Scholar 

  23. Sengupta S, Nagalingam A, Muniraj N, Bonner MY, Mistriotis P, Afthinos A, et al. Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene. 2017;36:5709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shen Z, Wen X-F, Lan F, Shen Z-Z, Shao Z-M. The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma. Clin Cancer Res. 2002;8:2085–90.

    CAS  PubMed  Google Scholar 

  25. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LGD, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004–8.

    Article  CAS  PubMed  Google Scholar 

  26. Jaleel M, McBride A, Lizcano JM, Deak M, Toth R, Morrice NA, et al. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett. 2005;579:1417–23.

    Article  CAS  PubMed  Google Scholar 

  27. Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23:833–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Benton R, St Johnston D. Drosophila PAR-1 and 14–3–3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell. 2003;115:691–704.

    Article  CAS  PubMed  Google Scholar 

  29. Amin N, Khan A, St Johnston D, Tomlinson I, Martin S, Brenman J, et al. LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye. Proc Natl Acad Sci USA. 2009;106:8941–6.

    Article  CAS  PubMed  Google Scholar 

  30. Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, et al. LKB1 regulates pancreatic beta cell size, polarity, and function. Cell Metab. 2009;10:296–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature. 2007;447:1017–20.

    Article  CAS  PubMed  Google Scholar 

  32. Bultot L, Horman S, Neumann D, Walsh MP, Hue L, Rider MH. Myosin light chains are not a physiological substrate of AMPK in the control of cell structure changes. FEBS Lett. 2009;583:25–28.

    Article  CAS  PubMed  Google Scholar 

  33. Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN, et al. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell. 2007;129:549–63.

    Article  CAS  PubMed  Google Scholar 

  34. Courchet J, Lewis TL, Lee S, Courchet V, Liou D-Y, Aizawa S, et al. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013;153:1510–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dorfman J, Macara IG. STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7. Mol Biol Cell. 2008;19:1614–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith DP, Spicer J, Smith A, Swift S, Ashworth A. The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase. Hum Mol Genet. 1999;8:1479–85.

    Article  CAS  PubMed  Google Scholar 

  37. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003;22:3062–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, et al. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 2003;22:5102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nezu J, Oku A, Shimane M. Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients. Biochem Biophys Res Commun. 1999;261:750–5.

    Article  CAS  PubMed  Google Scholar 

  40. Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D, et al. Analysis of the LKB1-STRAD-MO25 complex. J Cell Sci. 2004;117:6365–75.

    Article  CAS  PubMed  Google Scholar 

  41. Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DMF. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science. 2009;326:1707–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Collins SP, Reoma JL, Gamm DM, Uhler MD. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J. 2000;345:673–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, et al. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 byp90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth. J Biol Chem. 2001;276:19469–82.

    Article  CAS  PubMed  Google Scholar 

  44. Sapkota GP, Deak M, Kieloch A, Morrice N, Goodarzi AA, Smythe C, et al. Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Biochem J. 2002;368:507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sapkota GP, Boudeau J, Deak M, Kieloch A, Morrice N, Alessi DR. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. Biochem J. 2002;362:481–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Xie Z, Dong Y, Zhang M, Cui M-Z, Cohen RA, Riek U, et al. Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells. J Biol Chem. 2006;281:6366–75.

    Article  CAS  PubMed  Google Scholar 

  47. Bai Y, Zhou T, Fu H, Sun H, Huang B. 14-3-3 interacts with LKB1 via recognizing phosphorylated threonine 336 residue and suppresses LKB1 kinase function. FEBS Lett. 2012;586:1111–9.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang Y-L, Guo H, Zhang C-S, Lin S-Y, Yin Z, Peng Y, et al. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab. 2013;18:546–55.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang C-S, Jiang B, Li M, Zhu M, Peng Y, Zhang Y-L, et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 2014;20:526–40.

    Article  CAS  PubMed  Google Scholar 

  50. Chen J, Ou Y, Li Y, Hu S, Shao L-W, Liu Y. Metformin extends C. elegans lifespan through lysosomal pathway. Elife. 2017;6:e31268.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Zhang C-S, Hawley SA, Zong Y, Li M, Wang Z, Gray A, et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature. 2017;548:112–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tortelote GG, Reis RR, Almeida Mendes Fde, Abreu JG. Complexity of the Wnt/β‑catenin pathway. Searching for an activation model. Cell Signal. 2017;40:30–43.

    Article  CAS  PubMed  Google Scholar 

  53. O’Farrell F, Lobert VH, Sneeggen M, Jain A, Katheder NS, Wenzel EM, et al. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nat Cell Biol. 2017;19:1412–23.

    Article  PubMed  CAS  Google Scholar 

  54. Sebbagh M, Santoni M-J, Hall B, Borg J-P, Schwartz MA. Regulation of LKB1/STRAD localization and function by E-cadherin. Curr Biol. 2009;19:37–42.

    Article  CAS  PubMed  Google Scholar 

  55. Huo Y, Macara IG. The Par3-like polarity protein Par3L is essential for mammary stem cell maintenance. Nat Cell Biol. 2014;16:529–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468:701–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468:659–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lai D, Chen Y, Wang F, Jiang L, Wei C. LKB1 controls the pluripotent state of human embryonic stem cells. Cell Reprogram. 2012;14:164–70.

    Article  CAS  PubMed  Google Scholar 

  59. Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature. 2010;468:653–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li T, Liu D, Lei X, Jiang Q. Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway. Biochem Biophys Res Commun. 2017;482:1037–41.

    Article  CAS  PubMed  Google Scholar 

  61. Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget. 2015;6:29947–62.

    PubMed  PubMed Central  Google Scholar 

  62. Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D. Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res. 2012;14:R35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Seo MS, Kim JH, Kim HJ, Chang KC, Park SW. Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes. Toxicol Appl Pharmacol. 2015;284:113–24.

    Article  CAS  PubMed  Google Scholar 

  64. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137–63.

    Article  CAS  PubMed  Google Scholar 

  65. Xie Z, Dong Y, Zhang J, Scholz R, Neumann D, Zou M-H. Identification of the serine 307 of LKB1 as a novel phosphorylation site essential for its nucleocytoplasmic transport and endothelial cell angiogenesis. Mol Cell Biol. 2009;29:3582–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhu H, Moriasi CM, Zhang M, Zhao Y, Zou M-H. Phosphorylation of serine 399 in LKB1 protein short form by protein kinase Cζ is required for its nucleocytoplasmic transport and consequent AMP-activated protein kinase (AMPK) activation. J Biol Chem. 2013;288:16495–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu L, Siu F-M, Che C-M, Xu A, Wang Y. Akt blocks the tumor suppressor activity of LKB1 by promoting phosphorylation-dependent nuclear retention through 14-3-3 proteins. Am J Transl Res. 2012;4:175–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 2001;7:1307–19.

    Article  CAS  PubMed  Google Scholar 

  69. Xie Z, Dong Y, Scholz R, Neumann D, Zou M-H. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation. 2008;117:952–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Song P, Xie Z, Wu Y, Xu J, Dong Y, Zou M-H. Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem. 2008;283:12446–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Martin SG, St Johnston D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature. 2003;421:379–84.

    Article  CAS  PubMed  Google Scholar 

  72. Shelly M, Cancedda L, Heilshorn S, Sumbre G, Poo M-M. LKB1/STRAD promotes axon initiation during neuronal polarization. Cell. 2007;129:565–77.

    Article  CAS  PubMed  Google Scholar 

  73. Shen Y-AA, Chen Y, Dao DQ, Mayoral SR, Wu L, Meijer D, et al. Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent. Nat Commun. 2014;5:4991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fogarty S, Hardie DG. C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest. J Biol Chem. 2009;284:77–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bright NJ, Carling D, Thornton C. Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation. J Biol Chem. 2008;283:14946–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Houde VP, Ritorto MS, Gourlay R, Varghese J, Davies P, Shpiro N, et al. Investigation of LKB1 Ser431 phosphorylation and Cys433 farnesylation using mouse knockin analysis reveals an unexpected role of prenylation in regulating AMPK activity. Biochem J. 2014;458:41–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Towler MC, Fogarty S, Hawley SA, Pan DA, Martin DMA, Morrice NA, et al. A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis. Biochem J. 2008;416:1–14.

    Article  CAS  PubMed  Google Scholar 

  78. Denison FC, Hiscock NJ, Carling D, Woods A. Characterization of an alternative splice variant of LKB1. J Biol Chem. 2009;284:67–76.

    Article  CAS  PubMed  Google Scholar 

  79. Zheng B, Jeong JH, Asara JM, Yuan Y-Y, Granter SR, Chin L, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009;33:237–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Casimiro MC, Di Sante G, Di Rocco A, Loro E, Pupo C, Pestell TG, et al. Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis. Cancer Res. 2017;77:3391–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bartkova J, Lukas J, Müller H, Lützhøft D, Strauss M, Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994;57:353–61.

    Article  CAS  PubMed  Google Scholar 

  82. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  83. Inoki K, Zhu T, Guan K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.

    Article  CAS  PubMed  Google Scholar 

  84. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6:91–99.

    Article  CAS  PubMed  Google Scholar 

  85. Alexander A, Cai S-L, Kim J, Nanez A, Sahin M, MacLean KH, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA. 2010;107:4153–8.

    Article  CAS  PubMed  Google Scholar 

  86. Zheng X, Chi J, Zhi J, Zhang H, Yue D & Zhao J et al. Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration. Oncogene 2017. https://doi.org/10.1038/onc.2017.354.

    Article  PubMed  CAS  Google Scholar 

  87. Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 1999;59:2041–4.

    CAS  PubMed  Google Scholar 

  88. Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR. Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability. Biochem J. 2003;370:849–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nony P, Gaude H, Rossel M, Fournier L, Rouault J-P, Billaud M. Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene. 2003;22:9165–75.

    Article  CAS  PubMed  Google Scholar 

  90. Ylikorkala A, Avizienyte E, Tomlinson IP, Tiainen M, Roth S, Loukola A, et al. Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet. 1999;8:45–51.

    Article  CAS  PubMed  Google Scholar 

  91. Gaude H, Aznar N, Delay A, Bres A, Buchet-Poyau K, Caillat C, et al. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene. 2012;31:1582–91.

    Article  CAS  PubMed  Google Scholar 

  92. Lee S-W, Li C-F, Jin G, Cai Z, Han F, Chan C-H, et al. Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell. 2015;57:1022–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yang W-L, Zhang X, Lin H-K. Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development. Oncogene. 2010;29:4493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Geiss-Friedlander R, Melchior F. Concepts in sumoylation. A decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.

    Article  CAS  PubMed  Google Scholar 

  95. Ritho J, Arold ST, Yeh ETH. A critical SUMO1 modification of LKB1 regulates AMPK activity during energy stress. Cell Rep. 2015;12:734–42.

    Article  CAS  PubMed  Google Scholar 

  96. Konen J, Wilkinson S, Lee B, Fu H, Zhou W, Jiang Y, et al. LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol Biol Cell. 2016;27:1069–84.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Wilkinson S, Hou Y, Zoine JT, Saltz J, Zhang C, Chen Z, et al. Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity. Sci Rep. 2017;7:40929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008;283:27628–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bai B, Man AWC, Yang K, Guo Y, Xu C, Tse H-F, et al. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1. Oncotarget. 2016;7:39065–81.

    PubMed  PubMed Central  Google Scholar 

  100. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 2008;283:20015–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Price NL, Gomes AP, Ling AJY, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zu Y, Liu L, Lee MYK, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010;106:1384–93.

    Article  CAS  PubMed  Google Scholar 

  103. Tang X, Chen X-F, Wang N-Y, Wang X-M, Liang S-T & Zheng W et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation; 2017. https://doi.org/10.1161/CIRCULATIONAHA.117.028728.

    Article  CAS  PubMed  Google Scholar 

  104. Barbier-Torres L, Delgado TC, García-Rodríguez JL, Zubiete-Franco I, Fernández-Ramos D, Buqué X, et al. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer. Oncotarget. 2015;6:2509–23.

    Article  PubMed  Google Scholar 

  105. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995;81:641–50.

    Article  CAS  PubMed  Google Scholar 

  106. Liu Z, Dai X, Zhu H, Zhang M, Zou M-H. Lipopolysaccharides promote S-nitrosylation and proteasomal degradation of liver kinase B1 (LKB1) in macrophages in vivo. J Biol Chem. 2015;290:19011–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Schaur RJ. Basic aspects of the biochemical reactivity of 4-hydroxynonenal. Mol Asp Med. 2003;24:149–59.

    Article  CAS  Google Scholar 

  108. Mali VR, Palaniyandi SS. Regulation and therapeutic strategies of 4-hydroxy-2-nonenal metabolism in heart disease. Free Radic Res. 2014;48:251–63.

    Article  CAS  PubMed  Google Scholar 

  109. Dolinsky VW, Chan AYM, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JRB. Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation. 2009;119:1643–52.

    Article  CAS  PubMed  Google Scholar 

  110. Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. Post-translational modification of serine/threonine kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity. J Biol Chem. 2012;287:42400–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1-p70S6K-RPS6 signaling. Free Radic Biol Med. 2015;82:137–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Walz HA, Shi X, Chouinard M, Bue CA, Navaroli DM, Hayakawa A, et al. Isoform-specific regulation of Akt signaling by the endosomal protein WDFY2. J Biol Chem. 2010;285:14101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106:djt356.

    Article  PubMed  CAS  Google Scholar 

  114. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan C-W, et al. Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol. 2009;5:100–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Busch AM, Johnson KC, Stan RV, Sanglikar A, Ahmed Y, Dmitrovsky E, et al. Evidence for tankyrases as antineoplastic targets in lung cancer. BMC Cancer. 2013;13:211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang S-MA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461:614–20.

    Article  CAS  PubMed  Google Scholar 

  117. Korsse SE, Biermann K, Offerhaus GJA, Wagner A, Dekker E, Mathus-Vliegen EMH, et al. Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome. Carcinogenesis. 2013;34:1611–9.

    Article  CAS  PubMed  Google Scholar 

  118. Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013;23:143–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ikeda Y, Sato K, Pimentel DR, Sam F, Shaw RJ, Dyck JRB, et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J Biol Chem. 2009;284:35839–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang W, Wang Q, Wu Y, Moriasi C, Liu Z, Dai X, et al. Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation. 2014;129:1428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Su JY, Erikson E, Maller JL. Cloning and characterization of a novel serine/threonine protein kinaseexpressed in early Xenopus embryos. J Biol Chem. 1996;271:14430–37.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the German Research Foundation (DFG, SFB1348-A5).

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Kullmann, L., Krahn, M.P. Controlling the master—upstream regulation of the tumor suppressor LKB1. Oncogene 37, 3045–3057 (2018). https://doi.org/10.1038/s41388-018-0145-z

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