STK11
Serine/threonine kinase 11 also known as liver kinase B1 or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.
Expression
and DHT 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 of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.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.
Function
The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumour suppressor.LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase, a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of about 14 other kinases, comprising AMPK and AMPK-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. 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.
Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer. HER2/neu mice were engineered for loss of mammary gland expression of Lkb1 resulting in reduced latency of tumorgenesis. These mice developed mammary tumors that were highly metabolic and hyperactive for MTOR. Pre-clinical studies that simultaneously targeted mTOR and metabolism with AZD8055 and 2-DG, respectively inhibited mammary tumors from forming. Mitochondria function In control mice that did not have mammary tumors were not affected by AZD8055/2-DG treatments.
LKB1 catalytic deficient mutants found in Peutz–Jeghers syndrome activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. LKB1 catalytically deficient mutants have oncogenic properties.
Clinical significance
At least 51 disease-causing mutations in this gene have been discovered. Germline mutations in this gene have been associated with Peutz–Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas. Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast, intestinal, testicular, pancreatic and skin cancer.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.