INTRODUCTION
STK11 , named also LKB1 , has now been classified as a member of the calcium/calmodulin regulated kinase-like family, which is part of the Ca2+/calmodulin kinase group.
LKB1 is expressed ubiquitously in adult and fetal tissues, especially in pancreas, liver, testes, and skeletal muscle.
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LKB1 SIGNALING
LKB1 is activated by energetic stress.
LKB1 plays a key role in cell cycle arrest, tumor suppression, and cell polarity.
It forms a heterotrimeric complex with a pseudokinase STE20-related adaptor ( STRAD ) and the scaffolding protein, mouse protein 25 ( MO25 ) which play a crucial role in regulating LKB1 protein stability, kinase activity, and cellular localization. There are two functionally redundant isoforms (α and ß) of both STRAD and MO25.
The binding of STRAD to LKB1 substantially activates the autophosphorylation of LKB1 and hence its ability to phosphorylate downstream substrates. STRAD could also direct the subcellular localization of LKB1 by anchoring it in the cytoplasm. MO25 is a scaffolding protein of 40 kDa that stabilizes the binding of STRAD to LKB1, stimulating the catalytic activity of LKB1 ~10-fold.
Importantly, formation of the trimeric complex is required for full kinase activity of LKB1.
Loss of BRG1 is a prognostic indicator of non-small cell lung cancer; the lung cancer type also associated with loss of LKB. BRG1 is the essential catalytic helicase of the SWI/SNF chromatin remodeling complex, and is involved with epigenetic regulation of gene expression important in development, differentiation and carcinogenesis. Upon association with BRG1, LKB1 has been proposed to stimulate BRG1 and to have a role in BRG1 dependent growth arrest.
LKB1 phosphorylates the "T-loop" threonine in the kinase domain of the substrates, and this phosphorylation is required for their full activity. Via the substrates, LKB1 is implicated to regulate cellular energy management and polarity, and possibly other pathways as functions of some substrates are poorly characterized.
LKB1 signaling pathways mediated by the 14 substrate kinases.
Following the discovery of AMPK kinase family substrates, LKB1 has been implicated in various aspects of cellular metabolism and polarity control. Functions of some LKB1 substrates appear to overlap, as is exemplified by repression of CREB mediated transcription via TORC2 phosphorylation by both SIKs and AMPKs. Whereas SIK1 and SIK2 are inactivated through hormonal induction of cAMP and PKA, AMPK inactivates TORC2 in response to elevated AMP at least in cultured hepatocytes. Thus this pathway integrates cellular (AMPK) and hormonal (SIK) inputs to negatively regulate transcriptional events promoting synthesis of gluconeogenic enzymes.
Peutz-Jeghers Syndrome
A. Polyps are observed in the stomach and small intestine by gastroscopy. The schematic picture on the left points the typical localization of tumors. F, fundus; P, pylorus; D, duodenum.
B. Normal cellular composition of the gastrointestinal tract contains epithelium surrounded by connective tissue of lamina propria and layers of smooth muscle. In a histological HE-staining, PJS polyps distinctively display a branching smooth muscle core (black arrow) together with lamina propria and non-dysplastic epithelium.
