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STK3

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STK3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTK3, KRS1, MST2, serine/threonine kinase 3
External IDsOMIM: 605030; MGI: 1928487; HomoloGene: 48420; GeneCards: STK3; OMA:STK3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6788

56274

Ensembl

ENSG00000104375

ENSMUSG00000022329

UniProt

Q13188

Q9JI10

RefSeq (mRNA)

NM_001256312
NM_001256313
NM_006281

NM_019635
NM_001357821

RefSeq (protein)

NP_001243241
NP_001243242
NP_006272

NP_062609
NP_001344750

Location (UCSC)Chr 8: 98.37 – 98.94 MbChr 15: 34.88 – 35.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene.[5][6]

Background

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Protein kinase activation is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing agents. This protein kinase activation presumably allows cells to resist unfavorable environmental conditions. The yeast 'sterile 20' (Ste20) kinase acts upstream of the mitogen-activated protein kinase (MAPK) cascade that is activated under a variety of stress conditions. MST2 was first identified as a kinase that resembles budding yeast Ste20 (Creasy and Chernoff, 1996) and later as a kinase that is activated by the proapoptotic agents straurosporine and FAS ligand (MIM 134638) (Taylor et al., 1996; Lee et al., 2001).[supplied by OMIM][6]

Structure

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Human serine/threonine-protein kinase 3 (STK3, or MST2) is a 56,301 Da[7] monomer with three domains: a SARAH domain, composed of a long α-helix at the C-terminus that when dimerized, forms an antiparallel dimeric coiled-coil, an inhibitory domain, and a catalytic kinase domain at the N-terminus.[8] The SARAH (Salvador/RASSF/Hpo) domain has been found to mediate dimeric interactions between MST2 and RASSF enzymes, a class of tumor suppressors that serve an important role in activating apoptosis, as well as between MST2 and SAV1, a non-catalytic polypeptide responsible for bringing MST2 to an apoptotic pathway.[9][10] When the MST2 kinase domain is in its active state, a threonine residue residing on an alpha helix at the 180th position (T180) is autophosphorylated.[11]

Dimerized MST2 SARAH domains with labeled hydrophobic residues

Mechanism

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Activation

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STK3 is activated through autophosphorylation by dimerizing with itself or heterodimerizing with its homolog, MST1 (STK4).[12] Heterodimerization has been shown to exhibit a roughly six-fold weaker binding affinity than homodimerization with MST2, as well as lower kinase activity compared to both MST2/MST2 and MST1/MST1 homodimers.[10] In addition to activation by straurosporine and FAS ligand, STK3 has been found to be activated through dissociation of GLRX and Thioredoxin (Trx1) from STK3 under oxidative stress.[12] Recent studies have shown that when caspase 3 is activated during apoptosis, MST2 is cleaved, resulting in removal of the regulatory SARAH and inhibitory domains and thus regulation of MST2's kinase activity. Because cleavage by caspase 3 also cleaves off MST2's nuclear export signal, the MST2 kinase fragment can diffuse into the nucleus and phosphorylate Ser14 of histone H2B, promoting apoptosis.[10]

Inactivation

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Inactivation of MST2 can be accomplished through inhibition of MST2 homodimerization and autophosphorylation by c-Raf, which binds to the MST2 SARAH domain.[10]

MST2 substrates

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In the mammalian Hippo signaling pathway, MST2, along with its homolog MST1, serves as an upstream kinase whose catalytic activity is responsible for downstream events leading to downregulation of proliferation-associated genes and increased transcription of proapoptotic genes.[12] When MST2 binds to SAV1 through its SARAH domain, MST2 phosphorylates LATS1/LATS2 with the help of SAV1, MOB1A/MOB1B, and Merlin (protein). In turn, LATS1/LATS2 phosphorylates and inhibits YAP1, preventing its movement into the nucleus and activation of transcription of pro-proliferative, anti-apoptotic and migration-associated genes. In the cytoplasm, YAP1 is marked for degradation by the SCF complex.[13] Additionally, MST2 phosphorylates transcription factors in the FOXO (Forkhead box O) family, which diffuse into the nucleus and activate transcription of pro-apoptotic genes.[12]

Disease Relevance

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In many types of cancers, the proto-oncogene c-Raf binds to the SARAH domain of MST2 and prevents RASSF1A-mediated MST2 dimerization and subsequent downstream pro-apoptotic signaling.[14] Research has shown that in cells with loss of PTEN (gene), a tumor suppressor that is frequently mutated in cancers, Akt activity is upregulated, resulting in increased MST2 inactivation and undesirable cell proliferation.[15]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104375 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022329 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Taylor LK, Wang HC, Erikson RL (September 1996). "Newly identified stress-responsive protein kinases, Krs-1 and Krs-2". Proceedings of the National Academy of Sciences of the United States of America. 93 (19): 10099–104. Bibcode:1996PNAS...9310099T. doi:10.1073/pnas.93.19.10099. PMC 38343. PMID 8816758.
  6. ^ a b "Entrez Gene: STK3 serine/threonine kinase 3 (STE20 homolog, yeast)".
  7. ^ "PhosphoSitePlus: Serine/threonine-protein kinase 3 - Protein Information".
  8. ^ Liu G, Shi Z, Jiao S, Zhang Z, Wang W, Chen C, Hao Q, Hao Q, Zhang M, Feng M, Xu L, Zhang Z, Zhou Z, Zhang M (March 2014). "Structure of MST2 SARAH domain provides insights into its interaction with RAPL". Journal of Structural Biology. 185 (3): 366–74. doi:10.1016/j.jsb.2014.01.008. PMID 24468289.
  9. ^ Sánchez-Sanz G, Tywoniuk B, Matallanas D, Romano D, Nguyen LK, Kholodenko BN, Rosta E, Kolch W, Buchete NV (October 2016). "SARAH Domain-Mediated MST2-RASSF Dimeric Interactions". PLOS Computational Biology. 12 (10): e1005051. Bibcode:2016PLSCB..12E5051S. doi:10.1371/journal.pcbi.1005051. PMC 5055338. PMID 27716844.
  10. ^ a b c d Galan JA, Avruch J (Sep 2016). "MST1/MST2 Protein Kinases: Regulation and Physiologic Roles". Biochemistry. 55 (39): 5507–5519. doi:10.1021/acs.biochem.6b00763. PMC 5479320. PMID 27618557.
  11. ^ Ni L, et al. (Oct 2013). "Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5". Structure. 21 (10): 1757–1768. doi:10.1016/j.str.2013.07.008. PMC 3797246. PMID 23972470.
  12. ^ a b c d Lessard-Beaudoin M, Laroche M, Loudghi A, Demers MJ, Denault JB, Grenier G, Riechers SP, Wanker EE, Graham RK (November 2016). "Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process" (PDF). Neurobiology of Aging. 47: 50–62. doi:10.1016/j.neurobiolaging.2016.07.003. PMID 27552481. S2CID 3930860.
  13. ^ Meng Z, Moroishi T, Guan K (Jan 2016). "Mechanisms of Hippo pathway regulation". Genes Dev. 30 (1): 1–17. doi:10.1101/gad.274027.115. PMC 4701972. PMID 26728553.
  14. ^ Nguyen LK, Matallanas DG, Romano D, Kholodenko BN, Kolch W (Jan 2015). "Competing to coordinate cell fate decisions: the MST2-Raf-1 signaling device". Cell Cycle. 14 (2): 189–199. doi:10.4161/15384101.2014.973743. PMC 4353221. PMID 25607644.
  15. ^ Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W (Feb 2010). "Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt". Cancer Res. 70 (3): 1195–1203. doi:10.1158/0008-5472.CAN-09-3147. PMC 2880716. PMID 20086174.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: Q13188 (Serine/threonine-protein kinase 3) at the PDBe-KB.
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