STK11

Definition: STK11 (LKB1) is a serine-threonine protein kinase mutated in patients with an autosomal dominantly inherited cancer syndrome predisposing to multiple benign and malignant tumours, termed Peutz-Jeghers syndrome.

LKB1 has been implicated as a regulator of multiple biological processes and signaling pathways, including the control of cell-cycle arrest, p53-mediated apoptosis, Wnt signaling, transforming growth factor (TGF)-beta signaling, ras-induced cell transformation, and energy metabolism.

Functions

 STK11 cooperates with the Wnt-beta-catenin signalling in axis induction and modulates the expression of Wnt-responsive genes in both Xenopus embryos and mammalian cells.
 STK11 /XEEK1 acts upstream of beta-catenin in the Wnt-beta-catenin pathway in vivo.
 STK11 /XEEK1 regulates glycogen synthase kinase (GSK)3beta phosphorylation and it is physically associated in vivo with GSK3beta and protein kinase C (PKC)-zeta, a known GSK3 kinase.
 STK11 /XEEK1 is required for Wnt-beta-catenin signalling in frogs and mammals

 STK11 functions as a tumour suppressor perhaps by controlling cell polarity.

• Thus, Drosophila and human LKB1 may be functional homologues, suggesting that loss of cell polarity may contribute to tumour formation in individuals with Peutz-Jeghers syndrome.

Pathology

 germline mutations of the STK11 gene lead to Peutz-Jeghers syndrome

• with pulmonary adenocarcinoma (24054548)

 Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma. (25751324)

 somatic mutations in tumors (10079245):

• STK11-mutated pulmonary adenocarcinoma (25695224, 23995788, 22460425, 21191700, 12097271, 10079245)
• STK11-mutated cervical adenocarcinoma (10079245)

Animal models

 Lkb1(-/-) knock-out mice (12060709) - Nullizygosity provokes a poorly understood constellation of developmental perturbations in the mid-gestational mouse.

 Specific inhibition of XEEK1, the Xenopus orthologue of STK11 , engendered developmental anomalies - shortened body axis and defective dorsoanterior patterning - associated previously with aberrant Wnt signalling.

 LKB1-null mutant is defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression.

 The Drosophila par-4 homologue, lkb1, is required for the early A-P polarity of the oocyte, and for the repolarization of the oocyte cytoskeleton that defines the embryonic A-P axis.

 The level of AMPK phosphorylation increases during calcium-induced tight junction assembly and cell polarization and that this increase depends on the kinase activity of LKB1.

 JNK is the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo. Inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

Reviews

 Carling D. LKB1: a sweet side to Peutz-Jeghers syndrome? Trends Mol Med. 2006 Apr;12(4):144-7. PMID: 16530014

 Hardie DG. New roles for the LKB1—>AMPK pathway. Curr Opin Cell Biol. 2005 Apr;17(2):167-73. PMID: 15780593

 Spicer J, Ashworth A. LKB1 kinase: master and commander of metabolism and polarity. Curr Biol. 2004 May 25;14(10):R383-5. PMID: 15186763

 Baas AF, Smit L, Clevers H. LKB1 tumor suppressor protein: PARtaker in cell polarity. Trends Cell Biol. 2004 Jun;14(6):312-9. PMID: 15183188

 Yoo LI, Chung DC, Yuan J. LKB1, a master tumour suppressor of the small intestine and beyond. Nat Rev Cancer. 2002 Jul;2(7):529-35. PMID: 12094239

 Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Lett. 2003 Jul 3;546(1):159-65. PMID: 12829253

References

 Identification of Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma. Buryk MA, Picarsic JL, Creary SE, Shaw PH, Simons JP, Deutsch M, Monaco SE, Nikiforov YE, Witchel SF. Pediatr Dev Pathol. 2015 Jul-Aug;18(4):318-23. doi : 10.2350/15-01-1597-CR.1 PMID: 25751324