5wxn

Structural highlights

Disease

[STK11_HUMAN] Defects in STK11 are a cause of Peutz-Jeghers syndrome (PJS) [MIM:175200]. PJS is a rare hereditary disease in which there is predisposition to benign and malignant tumors of many organ systems. PJS is an autosomal dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer.^{[1] [2] [3] [4] [5] [6]} Defects in STK11 have been associated with testicular germ cell tumor (TGCT) [MIM:273300]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.^{[7] [8]} Note=Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans-differentiate into squamous cell carcinoma. Also able to promotes lung cancer metastasis, via both cancer-cell autonomous and non-cancer-cell autonomous mechanisms.

Function

[1433Z_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.^{[9] [10] [11] [12] [13]} [STK11_HUMAN] Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2: it thereby regulates inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neurons polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1 Also acts as a mediator p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways.^{[14] [15] [16] [17] [18] [19] [20] [21]}

References

1. ↑ Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998 Jan;18(1):38-43. PMID:9425897 doi:10.1038/ng0198-38
2. ↑ Nakagawa H, Koyama K, Miyoshi Y, Ando H, Baba S, Watatani M, Yasutomi M, Matsuura N, Monden M, Nakamura Y. Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome. Hum Genet. 1998 Aug;103(2):168-72. PMID:9760200
3. ↑ Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998 Jan 8;391(6663):184-7. PMID:9428765 doi:10.1038/34432
4. ↑ Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ, Lubinski J, Lindhout D, Halley DJ, de Rooij FW, Wilson JH. Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat. 1999;13(6):476-81. PMID:10408777 doi:<476::AID-HUMU7>3.0.CO;2-2 10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2
5. ↑ Scott RJ, Crooks R, Meldrum CJ, Thomas L, Smith CJ, Mowat D, McPhillips M, Spigelman AD. Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients. Clin Genet. 2002 Oct;62(4):282-7. PMID:12372054
6. ↑ Liu L, Du X, Nie J. A novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers syndrome patient significantly diminished p53 activity. Clin Res Hepatol Gastroenterol. 2011 Mar;35(3):221-6. doi:, 10.1016/j.clinre.2010.11.008. Epub 2011 Mar 15. PMID:21411391 doi:10.1016/j.clinre.2010.11.008
7. ↑ Avizienyte E, Roth S, Loukola A, Hemminki A, Lothe RA, Stenwig AE, Fossa SD, Salovaara R, Aaltonen LA. Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors. Cancer Res. 1998 May 15;58(10):2087-90. PMID:9605748
8. ↑ Ylikorkala A, Avizienyte E, Tomlinson IP, Tiainen M, Roth S, Loukola A, Hemminki A, Johansson M, Sistonen P, Markie D, Neale K, Phillips R, Zauber P, Twama T, Sampson J, Jarvinen H, Makela TP, Aaltonen LA. Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet. 1999 Jan;8(1):45-51. PMID:9887330
9. ↑ Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956
10. ↑ Zheng W, Zhang Z, Ganguly S, Weller JL, Klein DC, Cole PA. Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nat Struct Biol. 2003 Dec;10(12):1054-7. Epub 2003 Oct 26. PMID:14578935 doi:10.1038/nsb1005
11. ↑ Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004 Apr 21;23(8):1889-99. Epub 2004 Apr 8. PMID:15071501 doi:10.1038/sj.emboj.7600194
12. ↑ Ganguly S, Weller JL, Ho A, Chemineau P, Malpaux B, Klein DC. Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1222-7. Epub 2005 Jan 11. PMID:15644438 doi:0406871102
13. ↑ Gu YM, Jin YH, Choi JK, Baek KH, Yeo CY, Lee KY. Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett. 2006 Jan 9;580(1):305-10. Epub 2005 Dec 19. PMID:16376338 doi:S0014-5793(05)01485-7
14. ↑ Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 2001 Jun;7(6):1307-19. PMID:11430832
15. ↑ Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003 Jun 16;22(12):3062-72. PMID:12805220 doi:10.1093/emboj/cdg292
16. ↑ Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, Prescott AR, Clevers HC, Alessi DR. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 2003 Oct 1;22(19):5102-14. PMID:14517248 doi:10.1093/emboj/cdg490
17. ↑ Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell. 2004 Feb 6;116(3):457-66. PMID:15016379
18. ↑ Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG, Alessi DR. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004 Feb 25;23(4):833-43. Epub 2004 Feb 19. PMID:14976552 doi:10.1038/sj.emboj.7600110
19. ↑ Jaleel M, McBride A, Lizcano JM, Deak M, Toth R, Morrice NA, Alessi DR. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett. 2005 Feb 28;579(6):1417-23. PMID:15733851 doi:S0014-5793(05)00141-9
20. ↑ Zeng PY, Berger SL. LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation. Cancer Res. 2006 Nov 15;66(22):10701-8. PMID:17108107 doi:10.1158/0008-5472.CAN-06-0999
21. ↑ Hou X, Liu JE, Liu W, Liu CY, Liu ZY, Sun ZY. A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation. Oncogene. 2011 Jun 30;30(26):2933-42. doi: 10.1038/onc.2011.19. Epub 2011 Feb 14. PMID:21317932 doi:10.1038/onc.2011.19
22. ↑ Lu Y, Ding S, Zhou R, Wu J. Structure of the complex of phosphorylated liver kinase B1 and 14-3-3zeta. Acta Crystallogr F Struct Biol Commun. 2017 Apr 1;73(Pt 4):196-201. doi:, 10.1107/S2053230X17003521. Epub 2017 Mar 22. PMID:28368277 doi:http://dx.doi.org/10.1107/S2053230X17003521