STK11

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a is_associated_with::protein is_associated_with::kinase that in humans is encoded by the STK11 is_associated_with::gene.

Expression
is_associated_with::Testosterone 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, is_associated_with::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 adenine monophosphate-activated protein kinase (AMPK), a necessary element in cell is_associated_with::metabolism that is required for maintaining energy is_associated_with::homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK and is_associated_with::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.

Clinical significance
is_associated_with::Germline is_associated_with::mutations in this gene have been associated with is_associated_with::Peutz-Jeghers syndrome, an is_associated_with::autosomal dominant disorder characterized by the growth of is_associated_with::polyps in the gastrointestinal tract, pigmented is_associated_with::macules on the skin and mouth, and other is_associated_with::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.

Activation
LKB1 is activated is_associated_with::allosterically by binding to the pseudokinase STRAD and the adaptor protein is_associated_with::MO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activating AMPK and at least 12 other kinases that belong to the AMPK-related kinase family.

Structure
The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using is_associated_with::X-ray crystallography, and revealed the mechanism by which LKB1 is is_associated_with::allosterically activated. LKB1 has a structure typical of other protein is_associated_with::kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and is_associated_with::MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of is_associated_with::kinase activation, is held in place by is_associated_with::MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and is_associated_with::MO25.

Splice variants
Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice is_associated_with::isoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S). The short LKB1 variant is predominantly found in is_associated_with::testes.

Interactions
STK11 has been shown to interact with:


 * is_associated_with::CDC37,
 * * is_associated_with::Fyn
 * HSP90AA1
 * is_associated_with::LYK5, and
 * is_associated_with::SMARCA4.