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Serine/Threonine Kinase 11

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Contents

Function

Serine/Threonine-protein kinase (STK11) is a tumor suppressor that plays a role in cell metabolism, cell polarity, apoptosis and DNA damage response. STK11 controls the activity of the AMP-activated protein kinase (AMPK) family members as well as other non AMPK family members. This enzyme acts by phosphorylating the T-loop within AMPK and non AMPK members. The non AMPK family proteins that it phosphorylates are STRADA, PTEN and possibly p53/TP53. The AMPK family members it phosphorylates are PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2 and others but not MELK. STK11 acts as an upstream regulator by mediating phosphorylation and activation of the AMPK catalytic subunits PRKAA1 and PRKAA2. It also regulates activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage and inhibition of signaling pathway that promotes cell growth and proliferation when energy levels are low. Its inhibition of PI3K/Akt signaling activity in vein endothelial cells induces apoptosis in response to the oxidant peroxynitrite (in vitro). This enzyme also regulates UV-radiation induced DNA damage response and cell polarity by remodeling the actin cytoskeleton. [3].

Location

The STK11 gene is located on chromosome 19 on the p arm of the chromosome, also known as the short arm. The exact location is between base pair 1,205,799 and 1,228,435. Location is found in both the nucleus and the cytoplasm. In humans, when STK11 is over expressed it is mostly located in the nucleus, having limited amounts in the cytoplasm. When a cell is undergoing apoptosis, STK11 translocates into the mitochondria. STK11 is mostly expressed in the seminiferous tubules of the testes, showing higher expression in the fetal tissues than in adult tissues. [4]

Structure

STK11 has a molecular mass of approximately 50kDa and is the catalytically active unit of a heterotrimeric complex with STE20-related adaptor (STRAD) and mouse protein 25 (MO25). STRAD, a pseudokinase, induces a conformational change in STK11 to form the catalytically active state which transports STK11 from the nucleus to the cytoplasm. MO25, a scaffold protein, strengthens the interaction between STK11 and STRAD, and as a result enhances the kinase activity of STK11. [5] STK11 has a ATP binding site located at Lys78, a basic amino acid, and a nucleotide binding site (9 residues) consisting of hydrophobic amino acids (such as Gly, Leu, and Val), hydrophilic amino acids (such as Ser and Tyr), a basic amino acid (Lys), and an acidic amino acid (Glu). STK11 also has an active site at Asp176, which serves as a proton acceptor. [6]

Disease

The function of the STK11 is to suppress tumors. A mutation in this protein increases the risk of cancer and carcinomas (cancer arising from the epithelial tissue of internal organs primarily in the gastrointestinal (GI) tract). This is due to improper DNA repair mechanisms and resistance to apoptosis which are both associated to an accumulation of cyclin-dependent kinase inhibitor 1A (CDKN1A). CDKN1A regulates cell development during the G1 and S phase of interphase and activates cyclin-dependent kinase2 to regulate apoptosis. [7]. In addition to cancer, a germline mutation of STK11 also increases the chances of Peutz-Jeghers (PJ) syndrome, an autosomal genetic dominant mutation caused by a disruption of the kinase domain function. PJ syndrome is characterized by the growth of hamartomatous polyps in the GI tract, neoplasm, and discoloration of the skin and mouth. [8].


References

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Uniprot
  4. ↑ Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998 Jan 8;391(6663):184-7. PMID:9428765 doi:10.1038/34432
  5. ↑ STK11. Genetics Home Reference. National Library of Medicine.
  6. ↑ Gan RY, Li HB. Recent Progress on Liver Kinase B1 (LKB1): Expression, Regulation, Downstream Signaling and Cancer Suppressive Function. International Journal of Molecular Science. 2014 Sep; 15(9):16698-16718.
  7. ↑ Esteve-Puig R, Gil R, Gonzalez-Sanchez E, Bech-Serra JJ, Grueso J, Hernandez-Losa J, Moline T, Canals F, Ferrer B, Cortes J, Bastian B, Ramon Y Cajal S, Martin-Caballero J, Flores JM, Vivancos A, Garcia-Patos V, Recio JA. A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation. PLoS Genet. 2014 Oct 16;10(10):e1004721. doi: 10.1371/journal.pgen.1004721., eCollection 2014 Oct. PMID:25329316 doi:http://dx.doi.org/10.1371/journal.pgen.1004721
  8. ↑ Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998 Jan;18(1):38-43. PMID:9425897 doi:10.1038/ng0198-38
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