STK3

STK3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3WWS, 4HKD, 4L0N, 4LG4, 4LGD, 4OH9, 5BRM
Identifiers
Aliases	STK3, KRS1, MST2, serine/threonine kinase 3
External IDs	OMIM: 605030; MGI: 1928487; HomoloGene: 48420; GeneCards: STK3; OMA:STK3 - orthologs
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8q22.2 Start 98,371,228 bp[1] End 98,942,827 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 B3.1 Start 34,875,642 bp[2] End 35,179,067 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon tail of epididymis caput epididymis germinal epithelium placenta sural nerve optic nerve corpus epididymis seminal vesicula cartilage tissue Top expressed in tail of embryo dermis pineal gland Gonadal ridge cumulus cell blood left lung lobe zygote abdominal wall atrioventricular valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein dimerization activity protein serine/threonine kinase activator activity metal ion binding kinase activity protein serine/threonine kinase activity protein binding ATP binding magnesium ion binding protein kinase activity identical protein binding Cellular component cytoplasm cytosol nucleus protein-containing complex Biological process regulation of cell differentiation involved in embryonic placenta development positive regulation of extrinsic apoptotic signaling pathway via death domain receptors positive regulation of protein kinase B signaling intracellular signal transduction phosphorylation protein stabilization positive regulation of DNA-binding transcription factor activity positive regulation of JNK cascade hippo signaling endocardium development protein phosphorylation primitive hemopoiesis central nervous system development positive regulation of apoptotic process positive regulation of protein binding cell differentiation involved in embryonic placenta development positive regulation of fat cell differentiation negative regulation of organ growth neural tube formation negative regulation of canonical Wnt signaling pathway signal transduction negative regulation of cell population proliferation hepatocyte apoptotic process apoptotic process positive regulation of protein serine/threonine kinase activity regulation of mitotic cell cycle stress-activated protein kinase signaling cascade regulation of apoptotic process activation of protein kinase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 15: 34.88 – 35.18 Mb PubMed search [3] [4]
Wikidata
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Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene.^[5][6]

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]

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]

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

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]

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]

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