STK11
Serin/threoninska kinaza 11 (STK11) , znana I kao jetrena kinaza B1 (LKB1) ioli antigen bubrežnog carcinoma NY-REN-19 je proteinska kinaza koja je kod ljudi kodirana genom STK11.[5]
Ekspresija
[uredi | uredi izvor]Tretman testosteronom i DHT mišjih 3T3-L1 ili ljudskih SGBS adipocita tokom 24 sata značajno je smanjilo ekspresiju iRNK LKB1 preko androgenih receptora i posljedično smanjilo aktivaciju AMP-aktivirane protein-kinaze (AMPK), putem fosforilacije. Suprotno tome, tretman 17
Međutim, u ER-pozitivnoj ćelijskoj liniji karcinoma dojke MCF-7, estradiol je uzrokovao smanjenje doze transkripta LKB1 i ekspresije proteina, što je dovelo do značajnog smanjenja fosforilacije ciljanog AMKK LKB1. ER
Funkcija
[uredi | uredi izvor]Gen STK11/LKB1, koji kodira člana porodice serin/treonin kinaze, regulira polarmost ćelija i funkcionira kao supresor tumora.
LKB1 je primarna uzvodna kinaza adenozin-monofosfatom-aktivirane protein-kinaze (AMP-aktivirana protein-kinaza: AMPK), neophodni element za ćelijskii metabolizam koji je potreban za održavanje homeostazne energije. Sada je jasno da LKB1 ima efekte suzbijanja rasta, aktivirajući grupu od ~14 drugih kinaza, koje se sastoje od AMPK i kinaze povezane s AMPK. Aktivacija AMPK putem LKB1 suzbija rast i proliferaciju, kada su nivoi energije i hranljivih sastojaka oskudni. Aktivacija kinaza povezanih s AMPK od pomoću LKB1 ima vitalnu ulogu u održavanju polarnosti ćelija, čime inhibira neprimjereno širenje tumorskih ćelija. Iz dosadašnjih istraživanja pojavljuje se slika da gubitak LKB1 dovodi do dezorganizacije polarnosti ćelija i olakšava rast tumora u energetski nepovoljnim uslovima.
Gubitak aktivnosti LKB1 povezan je s visoko agresivnim HER2 + rakom dojke.[8] Miševi soja HER2/neu kreirani su za gubitak ekspresije mliječnih žlijezda Lkb1 što je rezultiralo smanjenom latencijom razvoja tumora. Ovi miševi razvili su tumore dojke koji su bili vrlo metabolički hiperaktivni za MTOR. Pretklinička ispitivanja koja su istovremeno ciljalaju mTOR i metabolizam sa AZD8055 (inhibitor mTORC1 i mTORC2) i 2-DG, odnosno inhibirali stvaranje tumora dojke.[9] Funkcije mitohondrija kod kontrolnih miševa koji nisu imali tumore dojke, tretmanim AZD8055/2-DG nisu bili pogođene.
Mutanti s katalitskim nedostatkom LKB1, pronađeni u Peutz-Jeghersovom sindromu, aktiviraju ekspresiju ciklina D1 regrutovanjem u odgovorne elemente u promotoru onkogena. Katalitski deficitarni mutanti LKB1 imaju onkogeno svojstvo.[10]
Klinički značaj
[uredi | uredi izvor]Mutacije germlina u ovom genu povezane su s Peutz – Jeghersovim sindromom, autosomno dominantnim poremećajem koji karakterizira rast polipa u gastrointestinalnom traktu, pigmentirane makule na koži i ustima i druge novotvorine.[11][12][13] Međutim, utvrđeno je da je gen LKB1 mutiran i u raku pluća sporadičnog porijekla, pretežno adenokarcinomima.[14] Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast,[8] intestinal, testicular, pancreatic and skin cancer.[15][16]
Aktivacija
[uredi | uredi izvor]LKB1 se aktivira alosterično vezanjem za pseudokinazu STRAD i adapterski protein MO25. Heterotrimerni kompleks LKB1-STRAD-MO25 predstavlja biološki aktivnu jedinicu koja je sposobna fosforilirati i aktivirati AMP-aktiviranu protein-kinazu (AMPK) i najmanje 12 drugih kinaza, koje pripadaju porodici kinaza povezanih s AMPK. Nekoliko novih prerađenih izoformi STRAD
Struktura
[uredi | uredi izvor]Kristalna struktura kompleksa LKB1-STRAD-MO25 razjašnjena je upotrebom rendgensk kristalografije,[18] i otkriven mehanizam pomoću kojeg se alosterno aktivira LKB1. LKB1 ima tipsku strukturu za druge kinazne, proteine s dva (mala i velika) režnja s obje strane liganda ATP-džepa za vezanje. STRAD i MO25 zajedno sarađuju na promociji aktivne konformacije LKB1. LKB1 aktivacijska petlja, kritični element u procesu aktivacije kinaza, sadrži MO25, objašnjavajući tako ogroman porast aktivnosti LKB1 u prisustvu STRAD i MO25.
- Aminokiselinska sekvenca
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MEVVDPQQLG | MFTEGELMSV | GMDTFIHRID | STEVIYQPRR | KRAKLIGKYL | ||||
| MGDLLGEGSY | GKVKEVLDSE | TLCRRAVKIL | KKKKLRRIPN | GEANVKKEIQ | ||||
| LLRRLRHKNV | IQLVDVLYNE | EKQKMYMVME | YCVCGMQEML | DSVPEKRFPV | ||||
| CQAHGYFCQL | IDGLEYLHSQ | GIVHKDIKPG | NLLLTTGGTL | KISDLGVAEA | ||||
| LHPFAADDTC | RTSQGSPAFQ | PPEIANGLDT | FSGFKVDIWS | AGVTLYNITT | ||||
| GLYPFEGDNI | YKLFENIGKG | SYAIPGDCGP | PLSDLLKGML | EYEPAKRFSI | ||||
| RQIRQHSWFR | KKHPPAEAPV | PIPPSPDTKD | RWRSMTVVPY | LEDLHGADED | ||||
| EDLFDIEDDI | IYTQDFTVPG | QVPEEEASHN | GQRRGLPKAV | CMNGTEAAQL | ||||
| STKSRAEGRA | PNPARKACSA | SSKIRRLSAC | KQQ |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
Varijante prerade
[uredi | uredi izvor]Uočene su i okarakterisane su alternativne prerađene transkripcijske varijante ovog gena. Postoje dvije glavne prerađene izoforme, koje se označavaju duga LKB1 (LKB1L) i kratka LKB1 (LKB1S). Kratka varijanta LKB1 uglavnom se nalazi u sjemenicima.
Interakcije
[uredi | uredi izvor]Pokazano je da STK11 ima interakcije sa:
Estrogen receptor alpha [24]
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000118046 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003068 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, et al. (januar 1998). "Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase". Nature Genetics. 18 (1): 38–43. doi:10.1038/ng0198-38. PMID 9425897. S2CID 28986057.
- ^ McInnes KJ, Brown KA, Hunger NI, Simpson ER (juli 2012). "Regulation of LKB1 expression by sex hormones in adipocytes". International Journal of Obesity. 36 (7): 982–5. doi:10.1038/ijo.2011.172. PMID 21876548.
- ^ Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, et al. (novembar 2011). "LKB1 expression is inhibited by estradiol-17
β in MCF-7 cells". The Journal of Steroid Biochemistry and Molecular Biology. 127 (3–5): 439–43. doi:10.1016/j.jsbmb.2011.06.005. PMID 21689749. S2CID 25221068. - ^ a b Andrade-Vieira R, Xu Z, Colp P, Marignani PA (22. 2. 2013). "Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways". PLOS ONE. 8 (2): e56567. doi:10.1371/journal.pone.0056567. PMC 3579833. PMID 23451056.
- ^ Andrade-Vieira R, Goguen D, Bentley HA, Bowen CV, Marignani PA (decembar 2014). "Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss". Oncotarget. 5 (24): 12738–52. doi:10.18632/oncotarget.2818. PMC 4350354. PMID 25436981.
- ^ Scott KD, Nath-Sain S, Agnew MD, Marignani PA (juni 2007). "LKB1 catalytically deficient mutants enhance cyclin D1 expression". Cancer Research. 67 (12): 5622–7. doi:10.1158/0008-5472.CAN-07-0762. PMID 17575127.
- ^ Hemminki A, Tomlinson I, Markie D, Järvinen H, Sistonen P, Björkqvist AM, et al. (januar 1997). "Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis". Nature Genetics. 15 (1): 87–90. doi:10.1038/ng0197-87. PMID 8988175. S2CID 8978401.
- ^ Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al. (januar 1998). "A serine/threonine kinase gene defective in Peutz-Jeghers syndrome". Nature. 391 (6663): 184–7. Bibcode:1998Natur.391..184H. doi:10.1038/34432. PMID 9428765. S2CID 4400728.
- ^ Scott R, Crooks R, Meldrum C (oktobar 2008). "Gene symbol: STK11. Disease: Peutz-Jeghers Syndrome". Human Genetics. 124 (3): 300. doi:10.1007/s00439-008-0551-3. PMID 18846624.
- ^ Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. (juli 2002). "Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung". Cancer Research. 62 (13): 3659–62. PMID 12097271.
- ^ Sanchez-Cespedes M (decembar 2007). "A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome". Oncogene. 26 (57): 7825–32. doi:10.1038/sj.onc.1210594. PMID 17599048.
- ^ "Distribution of somatic mutations in STK11". Catalogue of Somatic Mutations in Cancer. Wellcome Trust Genome Campus, Hinxton, Cambridge. Arhivirano s originala, 2. 4. 2012. Pristupljeno 11. 11. 2009.
- ^ Marignani PA, Scott KD, Bagnulo R, Cannone D, Ferrari E, Stella A, et al. (oktobar 2007). "Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization". Cancer Biology & Therapy. 6 (10): 1627–31. doi:10.4161/cbt.6.10.4787. PMID 17921699.
- ^ PDB 2WTK; Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM (decembar 2009). "Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation". Science. 326 (5960): 1707–11. Bibcode:2009Sci...326.1707Z. doi:10.1126/science.1178377. PMC 3518268. PMID 19892943.
- ^ a b Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR (mart 2003). "Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability". The Biochemical Journal. 370 (Pt 3): 849–57. doi:10.1042/BJ20021813. PMC 1223241. PMID 12489981.
- ^ Yamada E, Bastie CC (februar 2014). "Disruption of Fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase". PLOS ONE. 9 (2): e89604. Bibcode:2014PLoSO...989604Y. doi:10.1371/journal.pone.0089604. PMC 3934923. PMID 24586906.
- ^ Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D, et al. (decembar 2004). "Analysis of the LKB1-STRAD-MO25 complex". Journal of Cell Science. 117 (Pt 26): 6365–75. doi:10.1242/jcs.01571. PMID 15561763.
- ^ Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, et al. (juni 2003). "Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD". The EMBO Journal. 22 (12): 3062–72. doi:10.1093/emboj/cdg292. PMC 162144. PMID 12805220.
- ^ Marignani PA, Kanai F, Carpenter CL (august 2001). "LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest". The Journal of Biological Chemistry. 276 (35): 32415–8. doi:10.1074/jbc.C100207200. PMID 11445556.
- ^ Nath-Sain S, Marignani PA (juni 2009). "LKB1 catalytic activity contributes to estrogen receptor alpha signaling". Molecular Biology of the Cell. 20 (11): 2785–95. doi:10.1091/mbc.e08-11-1138. PMC 2688557. PMID 19369417.
Dopunska literatura
[uredi | uredi izvor]- Yoo LI, Chung DC, Yuan J (juli 2002). "LKB1--a master tumour suppressor of the small intestine and beyond". Nature Reviews. Cancer. 2 (7): 529–35. doi:10.1038/nrc843. PMID 12094239. S2CID 43512220.
- Baas AF, Smit L, Clevers H (juni 2004). "LKB1 tumor suppressor protein: PARtaker in cell polarity". Trends in Cell Biology. 14 (6): 312–9. doi:10.1016/j.tcb.2004.04.001. PMID 15183188.
- Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP (januar 2007). "The LKB1 tumor suppressor kinase in human disease". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1775 (1): 63–75. doi:10.1016/j.bbcan.2006.08.003. PMID 17010524.
- Bonaldo MF, Lennon G, Soares MB (septembar 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Bignell GR, Barfoot R, Seal S, Collins N, Warren W, Stratton MR (april 1998). "Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer". Cancer Research. 58 (7): 1384–6. PMID 9537235.
- Nakagawa H, Koyama K, Miyoshi Y, Ando H, Baba S, Watatani M, et al. (august 1998). "Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome". Human Genetics. 103 (2): 168–72. doi:10.1007/s004390050801. PMID 9760200. S2CID 23986504.
- Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, et al. (decembar 1998). "Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity". American Journal of Human Genetics. 63 (6): 1641–50. doi:10.1086/302159. PMC 1377635. PMID 9837816.
- Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J (mart 1999). "Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma". Oncogene. 18 (9): 1777–80. doi:10.1038/sj.onc.1202486. PMID 10208439.
- Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, et al. (juni 1999). "Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers". The American Journal of Pathology. 154 (6): 1835–40. doi:10.1016/S0002-9440(10)65440-5. PMC 1866632. PMID 10362809.
- Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ, et al. (1999). "Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families". Human Mutation. 13 (6): 476–81. doi:10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2. PMID 10408777.
- Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, et al. (novembar 1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". International Journal of Cancer. 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479.
- Collins SP, Reoma JL, Gamm DM, Uhler MD (februar 2000). "LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo". The Biochemical Journal. 345 Pt 3 (3): 673–80. doi:10.1042/0264-6021:3450673. PMC 1220803. PMID 10642527.
- Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, et al. (juni 2001). "Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth". The Journal of Biological Chemistry. 276 (22): 19469–82. doi:10.1074/jbc.M009953200. PMID 11297520.
- Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, et al. (juni 2001). "The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death". Molecular Cell. 7 (6): 1307–19. doi:10.1016/S1097-2765(01)00258-1. PMID 11430832.
- Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M (maj 2004). "Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene". Oncogene. 23 (22): 4037–40. doi:10.1038/sj.onc.1207502. PMID 15021901.
- Abed AA, Günther K, Kraus C, Hohenberger W, Ballhausen WG (novembar 2001). "Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz-Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597(insertion mark)598insIVS4)". Human Mutation. 18 (5): 397–410. doi:10.1002/humu.1211. PMID 11668633. S2CID 39255354.
- Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, et al. (decembar 2001). "STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas". The American Journal of Pathology. 159 (6): 2017–22. doi:10.1016/S0002-9440(10)63053-2. PMC 1850608. PMID 11733352.
