STK24 explained

Serine/threonine-protein kinase 24 is an enzyme that in humans is encoded by the STK24 gene[1] [2] [3] located in the chromosome 13, band q32.2. It is also known as Mammalian STE20-like protein kinase 3 (MST-3).[4] The protein is 443 amino acids long and its mass is 49 kDa.

Classification and discovery

The yeast 'Sterile 20' gene (STE20) functions upstream of the mitogen-activated protein kinase (MAPK) cascade. In mammals, protein kinases related to STE20 can be divided into 2 subfamilies based on their structure and regulation. Members of the PAK subfamily (see PAK3) contain a C-terminal catalytic domain and an N-terminal regulatory domain that has a CDC42-binding domain. In contrast, members of the GCK subfamily (MAP4K2), also called the Sps1 subfamily, have an N-terminal catalytic domain and a C-terminal regulatory domain without a CDC42-binding domain. STK24 belongs to the GCK subfamily of STE20-like kinases.[3]

The sterile 20 protein was first found in yeast.[5] The MST-20 related kinases family is growing, having 28 members divided into two groups - p21-activated kinase and germinal center kinase (GCK) families.[6] STK24 belongs to the germinal center kinase (GCK) III subfamily of sterile 20 kinases.

Function

Kinases of GCKIII subfamily are involved in regulation of multiple functions of the cells and interaction with programmed cell death 10 (CCM3).[7] CCM is a pathological vascular situation that, influencing the blood vessels in central nervous system (CNS), may cause stroke, seizure and even cerebral hemorrhage.[8] It has been shown that STK24 and STK25 operate in the same cardiovascular development pathway with CCM3. According to the results of the experiment by Zhang et al., lack of STK24 has no effect on the amount of neutrophils or leucocytes, as well as it does not affect the chemotaxis of neutrophils. Zhang et al. also the interaction between STK24 and CCM. Using tandem affinity purification with mass spectrometry, they found that CCM3 is the main protein that binds to STK24 in HEK293 cells.

STK24 operates on serine and threonine residues and, as a response to oxidative stress and caspase activity, develops cell death.

STK24 is activated by autophosphorylation at Thr-190 and phosphorylation at this site is essential for its function. Phosphorylation by protein kinase A activates the isoform B of STK24.

The mutagenesis of four residues in STK24 have been carried out. In position 18, the replacement of threonine (T) with alanine (A) causes the reduction of phosphorylation by PKA. the modification in positions 65, where lysine (K) is replaced with A, and the position 190, where T is replaced with A, affects the activity and autophosphorylation. In residue 321, the change of aspartic acid (D) to Asparagine (N) reveals as loss of proteolytic cleavage by caspases. Those residues may play an important role apoptotic signal transduction.

Structure and tissue distribution

STK24 has two subunits, 36kDa N-terminal subunit and 12 kDa C-terminal subunit. In the cells, STK24 is located in nucleus and less in cytoplasm and membrane. There are two isoforms of the protein, isoform A is ubiquitous and is expressed in 237 organs, isoform B is expressed in brain hippocampus and cerebral cortex.

Interactions

STK24 has been shown to interact with PDCD10,[9] [10] [11] TRAF3IP3,[11] STRN3,[10] [11] MOBKL3,[10] [11] STRN,[10] [11] SLMAP,[10] [11] PPP2R1A,[10] [11] CTTNBP2NL,[11] FAM40A[10] [11] and STRN4.[10] [11]

Further reading

Notes and References

  1. Schinkmann K, Blenis J . Cloning and characterization of a human STE20-like protein kinase with unusual cofactor requirements . The Journal of Biological Chemistry . 272 . 45 . 28695–703 . November 1997 . 9353338 . 10.1074/jbc.272.45.28695 . free .
  2. Zhou TH, Ling K, Guo J, Zhou H, Wu YL, Jing Q, Ma L, Pei G . Identification of a human brain-specific isoform of mammalian STE20-like kinase 3 that is regulated by cAMP-dependent protein kinase . The Journal of Biological Chemistry . 275 . 4 . 2513–9 . January 2000 . 10644707 . 10.1074/jbc.275.4.2513 . free .
  3. Web site: Entrez Gene: STK24 serine/threonine kinase 24 (STE20 homolog, yeast).
  4. Web site: STK24 - Serine/threonine-protein kinase 24 - Homo sapiens (Human) - STK24 gene & protein. www.uniprot.org . 2018-11-10.
  5. Ramer SW, Davis RW . A dominant truncation allele identifies a gene, STE20, that encodes a putative protein kinase necessary for mating in Saccharomyces cerevisiae . Proceedings of the National Academy of Sciences of the United States of America . 90 . 2 . 452–6 . January 1993 . 8421676 . 45681 . 10.1073/pnas.90.2.452 . free .
  6. Huang CY, Wu YM, Hsu CY, Lee WS, Lai MD, Lu TJ, Huang CL, Leu TH, Shih HM, Fang HI, Robinson DR, Kung HJ, Yuan CJ . Caspase activation of mammalian sterile 20-like kinase 3 (Mst3). Nuclear translocation and induction of apoptosis . The Journal of Biological Chemistry . 277 . 37 . 34367–74 . September 2002 . 12107159 . 10.1074/jbc.M202468200 . free .
  7. Fidalgo M, Fraile M, Pires A, Force T, Pombo C, Zalvide J . CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation . Journal of Cell Science . 123 . Pt 8 . 1274–84 . April 2010 . 20332113 . 10.1242/jcs.061341 . free .
  8. Zhang Y, Tang W, Zhang H, Niu X, Xu Y, Zhang J, Gao K, Pan W, Boggon TJ, Toomre D, Min W, Wu D . 6 . A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils . Developmental Cell . 27 . 2 . 215–226 . October 2013 . 24176643 . 3834565 . 10.1016/j.devcel.2013.09.021 .
  9. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
  10. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . 6 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .
  11. Goudreault M, D'Ambrosio LM, Kean MJ, Mullin MJ, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC . 6 . A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein . Molecular & Cellular Proteomics . 8 . 1 . 157–71 . January 2009 . 18782753 . 2621004 . 10.1074/mcp.M800266-MCP200 . free .

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