STK3

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

STK3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTK3, KRS1, MST2, serine/threonine kinase 3
External IDsOMIM: 605030 MGI: 1928487 HomoloGene: 48420 GeneCards: STK3
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

Background

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

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

Activation

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

Inactivation of MST2 can be accomplished in several ways, including inhibition of MST2 homodimerization and autophosphorylation by c-Raf, which binds to the MST2 SARAH domain,[10] and phosphorylation of the highly conserved Thr117 by Akt (protein kinase B), blocking autophosphorylation of Thr180, MST2 cleavage, kinase activity, and translocation to the nucleus.[13]

MST2 substrates

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.[14] 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

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.[15] 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.[16]

References
  1. GRCh38: Ensembl release 89: ENSG00000104375 - Ensembl, May 2017
  2. 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. doi:10.1073/pnas.93.19.10099. PMC 38343. PMID 8816758.
  6. "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. doi:10.1371/journal.pcbi.1005051. PMC 5055338. PMID 27716844.
  10. 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. 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. Kim D, Shu S, Coppola MD, Kaneko S, Yuan Z, Cheng JQ (Mar 2010). "Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway". PLOS ONE. 5 (3): e9616. doi:10.1371/journal.pone.0009616. PMC 2834758. PMID 20231902.
  14. 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.
  15. 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.
  16. 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
  • 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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