mercredi 3 août 2011

Mutated genes in cancer (3) – STK11/LKB1

STK11 (also known as LKB1)

In databases:

● Entrez ( 6794 or STK11
● Ensembl ( ENSG00000118046
● UniProt ( Q15831
● GeneCards ( STK11
● HGNC ( 11389 or STK11
● Enzyme Number (IUBMB): EC

Gene locus:


Protein name:

Serine/threonine kinase 11

Protein Size:

433 amino acids; about 49 kDa


The protein encoded by STK11 is a serine/threonine protein kinase, recently classified as a part of the Ca2+/ calmodulin kinase group of kinases. It phosphorylates and activates members of the adenosine monophosphate-activated protein kinase (AMPK)-related subfamily of protein kinases. In fact, the STK11/AMPK/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette is a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described.
STK11 activity is regulated by the pseudokinase STRADα and the scaffolding protein MO25α, resulting in the reorganization of non-polarized cells so they form asymmetrical apical and basal structures.
In addition, STK11 has been implicated in a range of processes including chromatin remodeling, cell cycle arrest (in G1), ras-induced cell transformation, p53-mediated apoptosis and Wnt signaling. STK11 is a tumor suppressor.

Cancer-related alterations

STK11 mutations have been associated with Peutz-Jeghers syndrome (PJS), which is an autosomal dominant syndrome characterized by a predisposition to benign and malignant tumors of many organ systems. The relative incidence is estimated to vary from 1/29 000 to 1/120 000 births. Features are multiple gastrointestinal tract hamartomous polyps, melanocytic macules on the skin and mouth, and an increased risk for various neoplasms in epithelia tissues. For example it has been estimated that there is a about 84, about 213 and about 520 fold increased risk of developing colon, gastric and small intestinal cancers respectively. PJS patients are also at an increased risk of developing cancers in the breast, lung, ovaries, uterus, cervix and testes.

A majority (60-70%) of PJS patients show germline mutations in STK11. Patients inherit mutations in one allele, and the remaining allele is later inactivated generally by LOH or sometimes somatic mutation. This biallelic inactivation of STK11 leads to a loss of tumor suppressor activity, thereby promoting tumorigenesis. Genetic locus heterogeneity may exist for this disease. A small percentage of families with no mutations in STK11 have been identified, however no other candidate genes that predispose to PJS have been identified to date.

Most STK11 germinal mutations identified to date are in the catalytic domain of the protein, indicating that kinase activity is likely essential for its function as a tumor suppressor. Several types of mutations including insertions, deletions, nonsense, missense and splice site alterations have been identified to date. One family has been identified with complete germline deletion of this gene.

Somatic mutations:    many of the polyps that develop in PJS show loss of heterozygosity and sometimes somatic mutations. Somatic mutations (mainly substitutions) rarely occur in sporadic tumors, with the exception of adenocarcinoma of the lung.  There are no mutational hotspots, although mutations are slightly more frequent for nucleotides corresponding to amino acids 37, 170 and 354.

References (open access)

The molecular mechanisms that underlie the tumor suppressor function of LKB1. Fan D, Ma C, Zhang H. Acta Biochim Biophys Sin (Shanghai). 2009 Feb;41(2):97-107.

LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y, Fang Z, Wu J, Han X, Zhang J, Sun Y, Wu G, Padera R, Chen H, Wong KK, Ge G, Ji H. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18892-7.

Peutz-Jeghers Syndrome. Amos CI, Frazier ML, Wei C, McGarrity TJ. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2001 Feb 23 [updated 2011 Feb 22].

The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Shackelford DB, Shaw RJ. Nat Rev Cancer. 2009 Aug;9(8):563-75.

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