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 17β-estradiolom povećao je iRNK LKB1-a, efekt posredovan alfa receptorima.[6]
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. ERα veže se za promotor STK11, neovisno o ligandu i ta interakcija je smanjena u prisustvu estradiola. Štaviše, u prisustvu estradiola, aktivnost promotora STK11 značajno je smanjena.[7]
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 STRADα koje različito utiču na aktivnost LKB1, složeni sklop, subćelijsku lokalizaciju LKB1 i aktivaciju AMPK puta ovisnog o LKB1.[17]
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
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, et al. (novembar 2011). "LKB1 expression is inhibited by estradiol-17β 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.
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- ^ "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.
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- ^ 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.
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