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Stk11

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Stk11

Serine/threonine kinase 11

Structure of the heterotrimeric LKB1-STRADα-MO25α complex.
Available structures
PDB Ortholog search: RCSB
Identifiers
2.7.11.1
RNA expression pattern

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.[1]

Expression

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, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.[2]

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.[3]

Function

The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase, 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 metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of other ~14 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.

Clinical significance

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.[4][5][6] Recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in lung, cervical, breast, intestinal, testicular, pancreatic and skin cancer.[7][8]

Activation

LKB1 is activated allosterically by binding to the pseudokinase STRAD and the adaptor protein 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 X-ray crystallography,[9] and revealed the mechanism by which LKB1 is allosterically activated. LKB1 has a structure typical of other protein kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of kinase activation, is held in place by MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and MO25 .

Splice variants

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

Interactions

STK11 has been shown to interact with MO25α/β and STRADα/β (LYK5) isoforms[10][11] SMARCA4,[12] CDC37[13] and Heat shock protein 90kDa alpha (cytosolic), member A1[13]

References

Further reading

External links

  • GeneReviews/NCBI/NIH/UW entry on Peutz-Jeghers syndrome
  • OMIM entries on Peutz-Jeghers syndrome

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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