Serine/threonine kinase 11 (STK11) also known asliver kinase B1 (LKB1) orrenal carcinoma antigen NY-REN-19 is aproteinkinase that in humans is encoded by theSTK11gene.[5]
Testosterone andDHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation ofAMPK by phosphorylation. In contrast,17β-estradiol treatment increased LKB1 mRNA, an effect mediated byoestrogen receptor alpha.[6]
However, in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK.ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.[7]
TheSTK11/LKB1 gene, which encodes a member of theserine/threonine kinase family, regulates cell polarity and functions as a tumour suppressor.
LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cellmetabolism that is required for maintaining energyhomeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK andAMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions.[8][9] A study in rats showed that LKB1 expression is upregulated in cardiomyocytes after birth and that LKB1 abundance negatively correlates with proliferation of neonatal rat cardiomyocytes.[10]
Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer.[11]HER2/neu mice were engineered for loss of mammary gland expression ofLkb1 resulting in reduced latency oftumorgenesis. These mice developed mammarytumors that were highly metabolic and hyperactive forMTOR. Pre-clinical studies that simultaneously targeted mTOR andmetabolism with AZD8055 (inhibitor ofmTORC1 andmTORC2) and2-DG, respectively inhibited mammary tumors from forming.[12] Mitochondria function In control mice that did not have mammary tumors were not affected by AZD8055/2-DG treatments.
LKB1 catalytic deficient mutants found inPeutz–Jeghers syndrome activate the expression ofcyclin D1 through recruitment to response elements within the promoter of theoncogene. LKB1 catalytically deficient mutants haveoncogenic properties.[13]
At least 51 disease-causing mutations in this gene have been discovered.[14]Germlinemutations in this gene have been associated with Peutz–Jeghers syndrome, anautosomal dominant disorder characterized by the growth ofpolyps in the gastrointestinal tract, pigmentedmacules on the skin and mouth, and otherneoplasms.[15][16][17] However, theLKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas.[18] Further, more recent studies have uncovered a large number of somatic mutations of theLKB1 gene that are present in cervical, breast,[11] intestinal, testicular, pancreatic and skin cancer.[19][20]
LKB1 has been implicated as a potential target for inducing cardiac regeneration after injury as the regenerative potential of cardiomyocytes is limited in adult mammals. Knockdown of Lkb1 in rat cardiomyocytes suppressed phosphorylation of AMPK and activated Yes-associated protein, which subsequently promoted cardiomyocyte proliferation.[21]
LKB1 is activatedallosterically by binding to the pseudokinaseSTRAD and the adaptor proteinMO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activatingAMPK and at least 12 other kinases that belong to the AMPK-related kinase family. Several novel splice isoforms of STRADα that differentially affect LKB1 activity, complex assembly, subcellular localization of LKB1 and the activation of the LKB1-dependent AMPK pathway.[22]
The crystal structure of the LKB1-STRAD-MO25 complex was elucidated usingX-ray crystallography,[23] and revealed the mechanism by which LKB1 isallosterically activated. LKB1 has a structure typical of other proteinkinases, with two (small and large) lobes on either side of the ligandATP-binding pocket.STRAD andMO25 together cooperate to promote LKB1 active conformation. The LKB1activation loop, a critical element in the process ofkinase activation, is held in place byMO25, thus explaining the huge increase in LKB1 activity in the presence ofSTRAD andMO25 .
Alternate transcriptionalsplice variants of this gene have been observed and characterized. There are two main spliceisoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S).[24][25] The short LKB1 variant is predominantly found intestes.
^"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. (January 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.PMID9425897.S2CID28986057.
^Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, et al. (November 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.PMID21689749.S2CID25221068.
^Hemminki A, Tomlinson I, Markie D, Järvinen H, Sistonen P, Björkqvist AM, et al. (January 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.PMID8988175.S2CID8978401.
^Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. (July 2002). "Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung".Cancer Research.62 (13):3659–62.PMID12097271.
Yoo LI, Chung DC, Yuan J (July 2002). "LKB1--a master tumour suppressor of the small intestine and beyond".Nature Reviews. Cancer.2 (7):529–35.doi:10.1038/nrc843.PMID12094239.S2CID43512220.
Baas AF, Smit L, Clevers H (June 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.PMID15183188.
Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP (January 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.PMID17010524.
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.PMID9537235.
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.PMID9760200.S2CID23986504.
