Regulation of the TSC Pathway by LKB1: Evidence of a Molecular Link Between Tuberous Sclerosis Complex and Peutz-Jeghers Syndrome

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2004 Jul 3

PMID 15231735

Citations 231

Authors

Michael N Corradetti

Ken Inoki

Nabeel Bardeesy

Ronald A DePinho

Kun-Liang Guan

Affiliations

Soon will be listed here.

Abstract

Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show that LKB1, the gene mutated in PJS, acts as a tumor suppressor by activating TSC2, the gene mutated in TSC. Like TSC2, LKB1 inhibits the phosphorylation of the key translational regulators S6K and 4EBP1. Furthermore, we show that LKB1 activates TSC2 through the AMP-dependent protein kinase (AMPK), indicating that LKB1 plays a role in cell growth regulation in response to cellular energy levels. Our results suggest that PJS and other benign tumor syndromes could be caused by dysregulation of the TSC2/mTOR pathway.

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References

Devroede G, Lemieux B, Masse S, Lamarche J, HERMAN P . Colonic hamartomas in tuberous sclerosis. Gastroenterology. 1988; 94(1):182-8. DOI: 10.1016/0016-5085(88)90628-2. View

Hawley S, Boudeau J, Reid J, Mustard K, Udd L, Makela T . Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003; 2(4):28. PMC: 333410. DOI: 10.1186/1475-4924-2-28. View

Young J, Povey S . The genetic basis of tuberous sclerosis. Mol Med Today. 1998; 4(7):313-9. DOI: 10.1016/s1357-4310(98)01245-3. View

Ylikorkala A, Rossi D, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M . Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 2001; 293(5533):1323-6. DOI: 10.1126/science.1062074. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Dennis P, Jaeschke A, Saitoh M, Fowler B, Kozma S, Thomas G . Mammalian TOR: a homeostatic ATP sensor. Science. 2001; 294(5544):1102-5. DOI: 10.1126/science.1063518. View

Hardie D, Hawley S . AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001; 23(12):1112-9. DOI: 10.1002/bies.10009. View

Kwiatkowski D, Zhang H, Bandura J, Heiberger K, Glogauer M, El-Hashemite N . A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet. 2002; 11(5):525-34. DOI: 10.1093/hmg/11.5.525. View

Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza G, Van Obberghen E . Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem. 2002; 277(31):27975-81. DOI: 10.1074/jbc.M204152200. View

10.

Manning B, Tee A, Logsdon M, Blenis J, Cantley L . Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002; 10(1):151-62. DOI: 10.1016/s1097-2765(02)00568-3. View

11.

Goncharova E, Goncharov D, Eszterhas A, Hunter D, Glassberg M, Yeung R . Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002; 277(34):30958-67. DOI: 10.1074/jbc.M202678200. View

12.

Inoki K, Li Y, Zhu T, Wu J, Guan K . TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002; 4(9):648-57. DOI: 10.1038/ncb839. View

13.

Potter C, Pedraza L, Xu T . Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002; 4(9):658-65. DOI: 10.1038/ncb840. View

14.

Bardeesy N, Sinha M, Hezel A, Signoretti S, Hathaway N, Sharpless N . Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature. 2002; 419(6903):162-7. DOI: 10.1038/nature01045. View

15.

Kenerson H, Aicher L, True L, Yeung R . Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 2002; 62(20):5645-50. View

16.

Kwiatkowski D . Tuberous sclerosis: from tubers to mTOR. Ann Hum Genet. 2003; 67(Pt 1):87-96. DOI: 10.1046/j.1469-1809.2003.00012.x. View

17.

Jacinto E, Hall M . Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol. 2003; 4(2):117-26. DOI: 10.1038/nrm1018. View

18.

Hong S, Leiper F, Woods A, Carling D, Carlson M . Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci U S A. 2003; 100(15):8839-43. PMC: 166400. DOI: 10.1073/pnas.1533136100. View

19.

Huang S, Houghton P . Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol. 2003; 3(4):371-7. DOI: 10.1016/s1471-4892(03)00071-7. View

20.

Eng C . PTEN: one gene, many syndromes. Hum Mutat. 2003; 22(3):183-98. DOI: 10.1002/humu.10257. View