Affinage

STK3

Serine/threonine-protein kinase 3 · UniProt Q13188

Length
491 aa
Mass
56.3 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STK3 (MST2) is a stress-responsive Ste20-family serine/threonine kinase that functions as a core component of the mammalian Hippo signaling pathway, integrating diverse upstream signals to control cell proliferation, apoptosis, autophagy, immune cell trafficking, and metabolic homeostasis. MST2 activates through SARAH-domain-mediated homodimerization that brings kinase domains into proximity for transautophosphorylation at Thr180; this mechanism is positively regulated by RASSF proteins (which block PP2A-mediated dephosphorylation and displace the inhibitory Raf-1 complex) and TRIM21-mediated K63-linked ubiquitination at Lys473, and negatively regulated by Akt (phosphorylation at T117/T384 disrupting dimerization and RASSF binding), PRMT5 (SARAH-domain methylation blocking dimerization), CDK1, and SCFβTrCP-mediated degradation (PMID:12554736, PMID:15618521, PMID:21199877, PMID:20086174, PMID:37905571, PMID:37354905, PMID:32994222). Active MST2 phosphorylates MOB1 at Thr74 to promote LATS1/2 activation and consequent YAP1 inactivation, and also directly phosphorylates substrates outside the canonical Hippo cascade including LC3-Thr50 (autophagosome–lysosome fusion), histone H2B-Ser14 (nucleolar DNA damage response and rDNA silencing), BNIP3 (mitophagy regulation in adipocytes), Runx2 (osteoblast differentiation inhibition), and Foxo1 (tumor suppression and regulatory T cell homeostasis) (PMID:18362890, PMID:18640976, PMID:25544559, PMID:29789391, PMID:33758424, PMID:30910359, PMID:38436783). Through MOB1 phosphorylation, MST2 also activates the Rac-DOCK8 axis to drive immune cell chemotaxis and, via TRAF6-ECSIT complex assembly, promotes mitochondrial ROS-dependent bactericidal activity (PMID:22412158, PMID:26414765).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 Medium

    Identification of MST2 as a stress-activated kinase established that a mammalian Ste20-family member responded selectively to apoptotic and stress stimuli rather than mitogens, setting it apart from growth-factor-activated MAP4K pathways.

    Evidence Biochemical purification, cloning, and in vitro kinase assays showing selective activation by stress agents

    PMID:8816758

    Open questions at the time
    • No physiological substrates identified
    • Activation mechanism unknown
    • Single lab, single paper
  2. 2003 High

    Demonstrating that MST2 activation requires trans-autophosphorylation at Thr180 and that caspase-3 cleavage locks the kinase in an active state resolved how MST2 is switched on during apoptosis and explained the irreversibility of its activation.

    Evidence Site-directed mutagenesis, in vitro phosphatase assays, and truncation mutants in mammalian cells

    PMID:12554736

    Open questions at the time
    • Structural basis for dimerization-dependent autophosphorylation not yet resolved
    • Identity of upstream activating signals unclear
  3. 2004 High

    Discovery that Raf-1 suppresses MST2 by preventing dimerization — independently of Raf kinase activity — revealed the first negative regulator and established MST2 as a key node connecting survival and apoptotic signaling.

    Evidence Proteomic analysis of Raf-1 complexes; siRNA knockdown; genetic rescue in Raf-1−/− cells across mouse and human systems

    PMID:15618521

    Open questions at the time
    • Molecular details of how Raf-1 blocks dimerization unknown
    • Whether other Raf family members participate not tested
  4. 2005 High

    Identification of LATS1/LATS2 as direct MST2 substrates at conserved activation-loop and hydrophobic-motif sites placed MST2 atop the mammalian Hippo kinase cascade, analogous to Drosophila Hippo.

    Evidence In vitro kinase assay with MS-based phosphosite mapping; SARAH-domain interaction analysis with WW45/Salvador

    PMID:15688006

    Open questions at the time
    • Whether MST2 phosphorylates LATS in vivo at endogenous levels not shown
    • How scaffold proteins control substrate selectivity not resolved
  5. 2007 High

    Demonstrating that RASSF1A displaces Raf-1 from MST2 and that the resulting MST2→LATS1→YAP1→p73 cascade drives PUMA transcription resolved the full signaling chain from tumor suppressor input to proapoptotic gene expression.

    Evidence Co-IP epistasis analysis, siRNA pathway ordering, reporter assays, and cell fractionation

    PMID:17889669

    Open questions at the time
    • Quantitative contribution of MST2 versus MST1 within this pathway not separated
    • In vivo relevance in tumor suppression not directly tested
  6. 2008 High

    Demonstrating that MST2 phosphorylates MOB1 at Thr74 — essential for MOB1–NDR/LATS ternary complex formation and kinase activation — identified the key phospho-switch that amplifies Hippo cascade output and links it to cell cycle control.

    Evidence In vitro kinase assays with MOB1 point mutants; siRNA; okadaic acid stimulation; cell cycle analysis in multiple cell types

    PMID:18328708 PMID:18362890

    Open questions at the time
    • Structural basis for phospho-MOB1 selectivity between LATS and NDR kinases unresolved
    • Relative contributions of MST1 versus MST2 to MOB1 phosphorylation in different tissues unknown
  7. 2009 High

    Liver-specific Mst1/Mst2 knockout showing YAP hyperactivation and hepatocellular carcinoma validated MST2 as a bona fide tumor suppressor in vivo and confirmed SARAH-mediated homodimerization as the obligate activation mechanism in a physiological setting.

    Evidence Conditional knockout mice with phospho-specific immunoblotting and tumor phenotyping

    PMID:19878874

    Open questions at the time
    • Individual contribution of MST2 versus MST1 not separable in double-KO
    • Tissue-specific differences in MST2 tumor suppression untested
  8. 2010 High

    Showing that Akt phosphorylates MST2 at T117 and T384 to inhibit homodimerization and promote Raf-1 binding established a direct cross-talk mechanism by which PI3K-Akt survival signaling suppresses the Hippo apoptotic arm.

    Evidence In vitro kinase assays, phospho-specific antibodies, Co-IP, and apoptosis assays with site-directed mutants

    PMID:20086174 PMID:20231902

    Open questions at the time
    • Whether Akt-mediated inhibition is relevant in all MST2-active tissues not examined
    • Phosphatases that reverse Akt-mediated modifications on MST2 not identified
  9. 2011 High

    Demonstrating that RASSF1A prevents PP2A-mediated dephosphorylation of MST2 Thr180 resolved how RASSF proteins sustain MST2 activity: not by direct activation but by phosphatase shielding.

    Evidence Dephosphorylation assays with PP2A; okadaic acid treatment; RASSF1A knockdown and rescue

    PMID:21199877

    Open questions at the time
    • Whether all RASSF family members share this protective mechanism unclear
    • The structural interface between RASSF1A and PP2A at MST2 unresolved
  10. 2012 High

    Genetic knockout revealed that MST1/MST2 control immune cell chemotaxis through MOB1-DOCK8-Rac activation, extending MST2 function beyond canonical Hippo-YAP signaling into immune cell migration.

    Evidence Mst1/Mst2 double knockout thymocytes; Rac1/RhoA GTP-loading assays; Co-IP of MOB1-DOCK8; migration assays

    PMID:22412158

    Open questions at the time
    • Direct phosphorylation of DOCK8 by MST2 not demonstrated
    • Whether MST2 uses MOB1-independent mechanisms in other immune cells unknown
  11. 2013 High

    Crystal structures of the MST2 kinase domain alone and in complex with RASSF5 SARAH domain revealed that RASSF5 disrupts MST2 homodimers when bound before phosphorylation but cannot inhibit already-active MST2, resolving the paradox of RASSF proteins acting as both activators and potential inhibitors depending on timing.

    Evidence X-ray crystallography with in vitro kinase assays and mutagenesis

    PMID:23972470

    Open questions at the time
    • Full-length MST2 structure not available
    • Dynamic interplay between homodimer and RASSF heterodimer in living cells not visualized
  12. 2014 High

    Discovery that STK3/STK4 directly phosphorylate LC3 at Thr50 — essential for autophagosome-lysosome fusion and bacterial clearance — established a Hippo-independent, cell-autonomous innate defense function for MST2.

    Evidence In vitro kinase assay, phosphomimetic rescue in STK3/4 KO cells, autophagy flux measurement, and bacterial clearance across multiple species

    PMID:25544559

    Open questions at the time
    • Whether MST2 phosphorylates other ATG8 family members unknown
    • Upstream signal triggering LC3 phosphorylation pathway not defined
  13. 2018 High

    Localization of MST2 to nucleoli and its ATM-dependent phosphorylation of histone H2B at Ser14 for rDNA transcriptional silencing revealed a chromatin-level DNA damage response function for MST2 distinct from cytoplasmic Hippo signaling.

    Evidence Subcellular fractionation, ChIP, ATM inhibitor treatment, MST2 knockout, and in vitro kinase assays

    PMID:29789391

    Open questions at the time
    • How MST2 is recruited to nucleoli mechanistically unresolved
    • Whether H2BS14p has roles beyond rDNA silencing not tested
  14. 2021 High

    Demonstrating that STK3/STK4 phosphorylate BNIP3 to regulate its dimerization and promote adipocyte mitophagy added metabolic homeostasis to MST2's functional repertoire, with loss of Stk3/4 increasing mitochondrial mass.

    Evidence Stk3/Stk4 double KO mice; BNIP3 phosphorylation/dimerization assays; mitochondrial mass measurement; high-fat diet metabolic phenotyping

    PMID:33758424

    Open questions at the time
    • Specific BNIP3 phosphorylation sites by MST2 not mapped
    • Whether MST2-BNIP3 axis operates in non-adipose tissues unknown
  15. 2023 High

    Identification of two post-translational switches — TRIM21-mediated K63-ubiquitination at K473 promoting MST2 dimerization and PRMT5-mediated SARAH-domain methylation at R461/R467 blocking it — revealed that MST2 homodimerization is controlled by competing ubiquitin and methyl marks.

    Evidence Direct ubiquitination assays with K473R mutant; in vitro methylation with PRMT5 inhibitor; functional kinase and YAP readouts; xenograft models

    PMID:37354905 PMID:37905571

    Open questions at the time
    • Whether TRIM21 and PRMT5 act on the same MST2 pool or in distinct compartments unknown
    • Interplay between ubiquitination and methylation not tested in a single system

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length MST2 structure capturing the autoinhibited-to-active conformational transition, the tissue-specific hierarchy of MST2 versus MST1, and the integration of its Hippo-dependent and Hippo-independent substrates into a unified signaling model remain unresolved.
  • No full-length structure of MST2 in autoinhibited or active conformation
  • Quantitative separation of MST1 versus MST2 contributions in most tissues lacking
  • How MST2 substrate selectivity is determined across its diverse target repertoire not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0140657 ATP-dependent activity 3
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-5357801 Programmed Cell Death 7 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1 R-HSA-9612973 Autophagy 1
Partners
LATS1MOB1APRMT5RAF1RASSF1RASSF5SAV1TRIM21
Complex memberships
MST1-MST2 heterodimerMST2-MOB1MST2-SAV1/WW45

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MST2 (Krs-2) is a Ste20-related serine/threonine kinase activated by a subset of stress conditions and apoptotic agents but not by mitogenic stimuli, establishing it as a stress-responsive kinase distinct from growth factor-activated kinases. Biochemical purification and cloning; in vitro kinase assays Proceedings of the National Academy of Sciences of the United States of America Medium 8816758
1998 MST2 phosphorylates the thyroid transcription factor TTF-1 at the same residues identified as major in vivo phosphorylation sites, identifying TTF-1 as the first substrate of this kinase class. In-gel kinase assay; in vitro kinase assay; site mapping The Journal of biological chemistry Medium 9430685
2003 MST2 kinase activity depends on autophosphorylation of Thr180 in an intermolecular (trans) reaction; caspase-3 cleavage of full-length MST2 generates a truncated form resistant to PP1/PP2A dephosphorylation, locking it in the active state during apoptosis. Site-directed mutagenesis; in vitro phosphatase assays; cell transfection with mutant constructs The Journal of biological chemistry High 12554736
2004 Raf-1 suppresses MST2 apoptotic activity by preventing its dimerization and activation-loop phosphorylation, independently of Raf-1 kinase activity; depletion of MST2 rescues apoptosis hypersensitivity in Raf-1-/- cells. Proteomic analysis of Raf-1 signaling complexes; siRNA knockdown; genetic rescue experiments Science (New York, N.Y.) High 15618521
2005 MST2 directly phosphorylates and activates LATS1 and LATS2 at two conserved sites: S909 (activation loop) and T1079 (hydrophobic motif); MST2 also directly interacts with hWW45/Salvador via its SARAH domain. In vitro kinase assay; mass spectrometry phosphosite mapping; deletion analysis; Co-IP Oncogene High 15688006
2006 MST1/MST2 heterodimerize with hSav/WW45 via conserved C-terminal coiled-coil (SARAH) domains; Mst kinases directly phosphorylate and stabilize hSav, with stabilization requiring physical interaction but not catalytic activity. Co-IP; in vitro phosphorylation; deletion mutagenesis; co-expression studies The FEBS journal High 16930133
2007 RASSF1A displaces the inhibitory Raf-1–MST2 complex, enabling MST2 activation; activated MST2 activates LATS1, which phosphorylates and releases YAP1 to translocate to the nucleus and associate with p73, driving transcription of the proapoptotic gene PUMA. Co-IP; epistasis analysis with siRNA; reporter assays; cell fractionation Molecular cell High 17889669
2008 MST1 and MST2 phosphorylate MOBKL1A/MOBKL1B (MOB1 homologs) in mitosis; this phosphorylation alters MOB1 binding to NDR-family kinases (promoting LATS1 binding and LATS1 activation-loop phosphorylation), and is sufficient to inhibit cell proliferation by slowing G1/S and mitotic exit. In vitro kinase assay; co-immunoprecipitation; okadaic acid/H2O2 stimulation; non-phosphorylatable mutant rescue; cell cycle analysis Current biology : CB High 18328708
2008 In human HEK293 cells, MST2 cooperates with LATS1/2 to phosphorylate YAP at Ser-127, requiring intact WW domains of YAP and PPxY motifs in LATS kinases; Mst2/Lats-mediated phosphorylation of YAP2 partially rescues cells from YAP2-induced apoptosis. Reconstitution in HEK293 cells; domain deletion mutants; phosphospecific immunoblotting; apoptosis assays The Journal of biological chemistry High 18640976
2008 MST2 phosphorylates MOB1 at Thr74; this phosphorylation is essential for formation of the MOB1–MST2–NDR1 ternary complex and for full NDR1 activation; Thr181 substitution also abolishes NDR1 activation but Thr74 is the primary MST2-phosphorylated site. In vitro kinase assay with MOB1 mutants; okadaic acid stimulation; siRNA knockdown; biochemical complex analysis Oncogene High 18362890
2009 MST2 undergoes activation through transautophosphorylation at its activation loop; SARAH-domain-mediated homodimerization is required for this autoactivation; MST2 is the Hippo ortholog that suppresses YAP phosphorylation in mouse liver, driving hepatocellular carcinoma upon loss of Mst1/2. Conditional knockout mice; phospho-specific immunoblotting; reexpression rescue; in vivo tumor models Cancer cell High 19878874
2009 RASSF2 binds MST1/MST2 as their most significant interaction partners, is phosphorylated by co-immunoprecipitating MST kinase activity, and protects MST2 from proteolytic degradation; RASSF2 expression increases MST2 levels while its loss decreases them. Co-IP at endogenous levels; mass spectrometry; siRNA knockdown; stable expression; immunofluorescence colocalization Oncogene Medium 19525978
2009 MST2, together with Furry (Fry) and MOB2, activates NDR1 kinase during early mitosis; MST2 depletion causes mitotic chromosome misalignment correctable by active NDR1, placing MST2 upstream of NDR1 in a chromosome alignment pathway. siRNA knockdown; epistasis (active NDR1 rescue); in vitro kinase assays; mitotic chromosome imaging Current biology : CB High 19327996
2010 Akt phosphorylates MST2 at T117 and T384; these phosphorylations inhibit MST2 homodimerization, promote its association with Raf-1 (inhibitory complex), and block binding to RASSF1A, thereby suppressing MST2 proapoptotic activity. In vitro kinase assay; site-directed mutagenesis; Co-IP; apoptosis assays; phospho-specific antibodies Cancer research High 20086174
2010 Akt phosphorylates MST2 at Thr117, inhibiting its caspase-3 cleavage, nuclear translocation, autophosphorylation at Thr180, and kinase activity in response to IGF-1-PI3K signaling. In vitro kinase assay; in vivo labeling; site-directed mutagenesis; immunoblotting PloS one Medium 20231902
2010 MST2 RNAi silencing leads to proteasome-dependent decrease in PP2A catalytic subunit levels, elevating inhibitory Raf-1 Ser259 phosphorylation and attenuating ERK pathway activation, revealing that MST2→LATS1/2 pathway maintains PP2A-C levels. RNAi; phospho-immunoblotting; proteasome inhibitor treatment; epistasis The Journal of biological chemistry Medium 20212043
2011 RASSF1A prevents PP2A-mediated dephosphorylation of MST1/MST2 at their activation-loop residues (Thr183/Thr180), shifting the kinases toward the active, phosphorylated state; RASSF1A also stabilizes MST2 protein. Dephosphorylation assays; PP2A knockdown; okadaic acid treatment; RASSF1A depletion The Journal of biological chemistry High 21199877
2011 Mutant K-Ras directly binds RASSF1A to activate the MST2-LATS1 apoptotic pathway; LATS1 sequesters Mdm2, stabilizing p53 and promoting apoptosis; wild-type K-Ras allele inhibits this pathway via AKT activation. Co-IP; siRNA epistasis; in vitro binding; tumor models; patient sample analysis Molecular cell High 22195963
2012 MST1 and MST2 control Rho GTPase (Rac1, RhoA) activation in thymocytes by phosphorylating MOB1, which then binds and activates the Rac1 guanyl nucleotide exchanger DOCK8, enabling SP thymocyte chemotaxis and thymic egress. Genetic double knockout; phospho-MOB1 immunoblotting; Rac1/RhoA GTP loading assays; Co-IP; migration assays The Journal of experimental medicine High 22412158
2013 Crystal structure of human MST2 kinase domain alone and bound to RASSF5 SARAH domain reveals that MST2 activates via transautophosphorylation requiring SARAH-mediated homodimerization; RASSF5 disrupts the MST2 homodimer and blocks autoactivation when bound before phosphorylation, but does not inhibit already-activated MST2. X-ray crystallography; in vitro kinase assays; mutagenesis Structure (London, England : 1993) High 23972470
2014 The crystal structure of human MST2 SARAH domain reveals an antiparallel homodimeric coiled coil; structure-guided mutagenesis identifies interface residues critical for both homodimerization and hetero-interaction with RAPL/RASSF5; SARAH-mediated homodimerization and RAPL hetero-interaction are both required for full MST2 activation and apoptotic function in T cells. X-ray crystallography; mutagenesis; biochemical binding assays; cellular apoptosis assays Journal of structural biology High 24468289
2014 A competing protein interaction circuit coordinates MST2-LATS and MEK-ERK pathways: Akt phosphorylation of MST2 and a LATS1 feedback phosphorylation of Raf-1 Ser259 enable Raf-1 to suppress both MST2 and MEK signaling; mutation of Raf-1 Ser259 drives simultaneous apoptosis and proliferation signals, corrected by MST2 co-downregulation. Mathematical modeling combined with experimental validation; mutagenesis; Co-IP; cell biology assays Nature cell biology High 24929361
2014 STK3 (MST2) and STK4 (MST1) directly phosphorylate LC3 at threonine 50; this phosphorylation is essential for autophagosome-lysosome fusion; constitutively phospho-mimetic LC3-T50E reverses the autophagy block in STK3/STK4-deficient cells and restores clearance of intracellular bacteria. In vitro kinase assay; phospho-site mapping; STK3/4 knockout; phosphomimetic mutant rescue; autophagy flux assays; bacterial clearance assay; multi-species conservation study Molecular cell High 25544559
2014 Mst1 stabilizes Foxo1/3 transcription factors by direct phosphorylation and by attenuating TCR-induced Akt activation in T cells, thereby promoting Foxp3 expression and regulatory T cell development. Mst1 knockout mice; in vitro kinase assay; phospho-immunoblotting; Treg functional assays; bone marrow chimera Journal of immunology (Baltimore, Md. : 1950) Medium 24453252
2012 c-Abl kinase phosphorylates MST2 at the evolutionarily conserved Tyr81 within the kinase domain; this phosphorylation disrupts MST2-Raf-1 interaction, enhances MST2 homodimerization, and thereby activates MST2 to induce neuronal cell death. In vitro kinase assay; co-immunoprecipitation; cell death assays; mutagenesis PloS one Medium 22590567
2015 MST1 and MST2 promote TLR-triggered TRAF6-ECSIT complex assembly and mitochondrial trafficking to phagosomes by activating the GTPase Rac, enabling ROS production and bactericidal activity. Mst1/Mst2 knockout; Rac GTP loading assays; Co-IP of TRAF6-ECSIT; mitochondrial imaging; bacterial killing assays Nature immunology High 26414765
2016 Co-crystal structure of MST2 with inhibitor XMU-MP-1 confirms on-target binding; XMU-MP-1 blocks MST1/2 kinase activity, activates downstream YAP, and promotes tissue regeneration in vivo. Co-crystal structure; enzyme-linked immunosorbent assay-based high-throughput biochemical assay; in vivo mouse models Science translational medicine High 27535619
2016 Mst1 and Mst2 form kinase-inactive heterodimers via SARAH domains; H-Ras, via ERK-dependent signaling, strongly promotes Mst1/Mst2 heterodimerization; cells lacking Mst1 (incapable of forming heterodimers) resist H-Ras-mediated transformation and maintain active Hippo signaling. Co-IP; SARAH-domain mutagenesis; kinase activity assays; transformation assays; genetic cell lines Current biology : CB High 27238285
2016 CDK1 phosphorylates MST2 at Ser385 during mitosis (G2/M); this phosphorylation does not affect kinase activity or YAP signaling but reduces MST2 tumor suppressor activity; phosphorylation-deficient MST2-S385A has higher activity in suppressing proliferation and tumorigenesis. In vitro kinase assay; in vivo phospho-labeling; mutagenesis; colony formation and anchorage-independent growth; xenograft models Cellular signalling Medium 27566175
2018 MST2 localizes to nucleoli and, in an ATM-dependent manner, phosphorylates histone H2B at Ser14 (H2BS14p) in response to DNA damage; H2BS14p marks transcriptionally inactive nucleolar chromatin and is necessary for rDNA transcriptional silencing and genomic integrity maintenance. Subcellular fractionation/immunofluorescence; ChIP; ATM inhibitor; MST2 knockout; in vitro kinase assays The EMBO journal High 29789391
2018 Mst1 and Mst2 sense IL-2 signals in regulatory T cells to amplify STAT5 activation; mechanistically, Mst1 associates with the cytoskeletal DOCK8-LRCH module, regulates Rac GTPase activity, and promotes Treg cell migration and access to IL-2. Quantitative proteomics; Mst1/2 conditional KO; STAT5 phospho-flow; Co-IP; migration assays; Rac activity assays Immunity High 30413360
2019 MST2 directly phosphorylates Runx2 at Ser339 and Ser370; phosphorylation inhibits Runx2 transcriptional activity and osteoblast differentiation; the interaction requires SAV1's WW domain and an amino acid 292–445 region of Runx2 containing a PY motif. Co-IP; in vitro kinase assay; mass spectrometry; mutagenesis; OSE luciferase reporter; osteoblast differentiation assays Biochemical and biophysical research communications High 30910359
2020 Increasing kinase domain proximity—via SARAH domain homodimerization, membrane recruitment, or SAV1 complex formation—is sufficient to trigger MST2 autophosphorylation; each upstream input uses this common mechanism to activate MST2. Chemically induced dimerization; single-molecule pulldown; in vitro biochemistry; cell-based assays with mutagenesis The Journal of biological chemistry High 32994222
2021 STK3 and STK4 increase adipocyte mitophagy by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3; genetic inactivation of Stk3/Stk4 increases mitochondrial mass and function in adipose tissues. Stk3/Stk4 double knockout; BNIP3 phosphorylation and dimerization assays; mitochondrial mass/function measurements; high-fat diet metabolic studies Nature metabolism High 33758424
2022 SCFβTrCP E3 ubiquitin ligase binds MST2 via a non-canonical degradation motif and mediates its proteasomal degradation; stiffer extracellular matrix enhances MST2 degradation through integrin-linked kinase (ILK) and actomyosin stress fibers. Co-IP with SCFβTrCP; siRNA knockdown of βTrCP; site-directed mutagenesis; molecular dynamics simulation; ECM stiffness manipulation Biochimica et biophysica acta. General subjects Medium 36044955
2023 TRIM21 directly interacts with MST2 and ubiquitinates it at lysine 473 via K63-linkage, promoting MST2 homodimerization and enhanced kinase activity, leading to YAP inactivation. Co-IP; ubiquitination assay; site-directed mutagenesis (K473); tumor organoids; mouse models Cell chemical biology High 37354905
2023 PRMT5 symmetrically di-methylates MST2 at arginine 461 and arginine 467 in its SARAH domain; this methylation suppresses MST2 autophosphorylation and kinase activity by blocking SARAH-mediated homodimerization, thereby inactivating Hippo signaling in pancreatic cancer. In vitro methylation assay; site-directed mutagenesis; autophosphorylation assays; PRMT5 inhibitor (GSK3326595); xenograft models The EMBO journal High 37905571
2014 AIF (apoptosis-inducing factor) physically interacts with STK3 and enhances STK3 phosphorylation at Thr180, positively regulating its activity. Co-immunoprecipitation; phospho-specific immunoblotting; overexpression in RCC cell lines PloS one Low 24992339
2025 STK3 directly phosphorylates GSK-3β, promoting GSK-3β degradation and β-catenin nuclear accumulation, thereby activating Wnt signaling in gastric cancer; STK3 is also transcriptionally upregulated by YAP1, forming a positive feedback loop. Co-immunoprecipitation; in vitro kinase assay; ChIP-qPCR; gene knockout mouse models; functional rescue assays; CETSA Molecular cancer Medium 40604818
2024 STK3 kinase activation by cellular ROS induces autophosphorylation, phosphorylates FOXO1 at Ser212 promoting nuclear translocation, and upregulates TP53INP1 and P21 transcription to suppress ESCC cell proliferation. ROS stimulation; co-immunoprecipitation; immunofluorescence; RNA-seq; ChIP; in vitro kinase assay; xenograft models Cellular oncology (Dordrecht, Netherlands) Medium 38436783

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer cell 791 19878874
2005 The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 499 15688006
2010 Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America 473 20080598
2011 Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proceedings of the National Academy of Sciences of the United States of America 403 22042863
2008 MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Current biology : CB 357 18328708
2007 RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Molecular cell 342 17889669
2016 Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Science translational medicine 330 27535619
2008 Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). The Journal of biological chemistry 308 18640976
2004 Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science (New York, N.Y.) 267 15618521
2006 Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. The FEBS journal 227 16930133
2015 Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nature immunology 208 26414765
2014 Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Molecular cell 156 25544559
2012 The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. The Journal of experimental medicine 142 22412158
2007 Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Molecular carcinogenesis 142 17538946
2015 ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Science translational medicine 138 26446957
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 134 8816758
2014 Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nature cell biology 127 24929361
2014 Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. Journal of immunology (Baltimore, Md. : 1950) 124 24453252
2011 Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Molecular cell 117 22195963
2009 Crucial role for Mst1 and Mst2 kinases in early embryonic development of the mouse. Molecular and cellular biology 115 19786569
2017 Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO molecular medicine 104 27940445
2018 Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity 97 30413360
2009 MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes. Current biology : CB 94 19327996
2011 The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2. The Journal of biological chemistry 93 21199877
2010 Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer research 90 20086174
2013 Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5. Structure (London, England : 1993) 82 23972470
2013 Mst1 and Mst2 kinases: regulations and diseases. Cell & bioscience 80 23985272
2016 MST1/MST2 Protein Kinases: Regulation and Physiologic Roles. Biochemistry 76 27618557
2009 RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene 69 19525978
2010 Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer research 67 20145135
2014 HGF induces epithelial-to-mesenchymal transition by modulating the mammalian hippo/MST2 and ISG15 pathways. Journal of proteome research 63 24766643
2003 Regulation of mammalian STE20-like kinase 2 (MST2) by protein phosphorylation/dephosphorylation and proteolysis. The Journal of biological chemistry 58 12554736
2015 miR-155-dependent regulation of mammalian sterile 20-like kinase 2 (MST2) coordinates inflammation, oxidative stress and proliferation in vascular smooth muscle cells. Biochimica et biophysica acta 52 25892184
2005 Taming the Hippo: Raf-1 controls apoptosis by suppressing MST2/Hippo. Cell cycle (Georgetown, Tex.) 51 15701972
2012 Regulation of neuronal cell death by c-Abl-Hippo/MST2 signaling pathway. PloS one 49 22590567
2021 STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure. Nature metabolism 48 33758424
2008 Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene 48 18362890
1992 Autoregulation of the yeast lysyl-tRNA synthetase gene GCD5/KRS1 by translational and transcriptional control mechanisms. Cell 48 1505029
2005 Schizosaccharomyces pombe mst2+ encodes a MYST family histone acetyltransferase that negatively regulates telomere silencing. Molecular and cellular biology 43 16199868
2010 Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PloS one 42 20231902
2013 Functional role of Mst1/Mst2 in embryonic stem cell differentiation. PloS one 41 24224013
2017 The Histone Acetyltransferase Mst2 Protects Active Chromatin from Epigenetic Silencing by Acetylating the Ubiquitin Ligase Brl1. Molecular cell 38 28648780
2010 Mammalian Ste20-like kinase (Mst2) indirectly supports Raf-1/ERK pathway activity via maintenance of protein phosphatase-2A catalytic subunit levels and consequent suppression of inhibitory Raf-1 phosphorylation. The Journal of biological chemistry 37 20212043
2015 Mst2 Controls Bone Homeostasis by Regulating Osteoclast and Osteoblast Differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 25761670
2023 TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell chemical biology 32 37354905
2014 The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy. The Journal of biological chemistry 32 25035424
2018 MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B. The EMBO journal 31 29789391
2021 Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Molecular therapy : the journal of the American Society of Gene Therapy 29 34450249
2013 The differential effects of wild-type and mutated K-Ras on MST2 signaling are determined by K-Ras activation kinetics. Molecular and cellular biology 27 23459937
2021 Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia. Journal of medicinal chemistry 26 34807584
2016 H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization. Current biology : CB 26 27238285
2023 MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression. The EMBO journal 25 37905571
2020 Hippo kinases MST1 and MST2 control the differentiation of the epididymal initial segment via the MEK-ERK pathway. Cell death and differentiation 25 32332916
2017 The histone acetyltransferase Mst2 sustains the biological control potential of a fungal insect pathogen through transcriptional regulation. Applied microbiology and biotechnology 25 29275430
2015 Competing to coordinate cell fate decisions: the MST2-Raf-1 signaling device. Cell cycle (Georgetown, Tex.) 25 25607644
2019 STK3/4 Expression Is Regulated in Uterine Endometrial Cells during the Estrous Cycle. Cells 20 31847471
2016 Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation. Cell death and differentiation 20 26891695
1991 A PMR2 tandem repeat with a modified C-terminus is located downstream from the KRS1 gene encoding lysyl-tRNA synthetase in Saccharomyces cerevisiae. Molecular & general genetics : MGG 19 2046655
2014 Mst1 and mst2 are essential regulators of trophoblast differentiation and placenta morphogenesis. PloS one 18 24595170
1998 Identification of the thyroid transcription factor-1 as a target for rat MST2 kinase. The Journal of biological chemistry 17 9430685
2020 STK3 Suppresses Ovarian Cancer Progression by Activating NF-κB Signaling to Recruit CD8+ T-Cells. Journal of immunology research 15 33062724
2016 SARAH Domain-Mediated MST2-RASSF Dimeric Interactions. PLoS computational biology 15 27716844
2015 LC3 is a novel substrate for the mammalian Hippo kinases, STK3/STK4. Autophagy 15 25996575
2020 MST2 silencing induces apoptosis and inhibits tumor growth for estrogen receptor alpha-positive MCF-7 breast cancer. Toxicology and applied pharmacology 14 33007383
2014 Structure of MST2 SARAH domain provides insights into its interaction with RAPL. Journal of structural biology 14 24468289
2023 Effect of STK3 on proliferation and apoptosis of pancreatic cancer cells via PI3K/AKT/mTOR pathway. Cellular signalling 13 36871796
2022 High MST2 expression regulates lens epithelial cell apoptosis in age-related cataracts through YAP1 targeting GLUT1. Archives of biochemistry and biophysics 13 35452623
2020 Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling. The Journal of biological chemistry 13 32994222
2013 Hippo signaling components, Mst1 and Mst2, act as a switch between self-renewal and differentiation in Xenopus hematopoietic and endothelial progenitors. The International journal of developmental biology 13 23873372
2024 YAP activation in liver macrophages via depletion of MST1/MST2 enhances liver inflammation and fibrosis in MASLD. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 39215627
2015 MST2-RASSF protein-protein interactions through SARAH domains. Briefings in bioinformatics 11 26443615
2022 Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner. Cell death & disease 10 35941108
2014 AIF downregulation and its interaction with STK3 in renal cell carcinoma. PloS one 10 24992339
2018 STK3 is a therapeutic target for a subset of acute myeloid leukemias. Oncotarget 9 29876001
2017 Spatial regulation of ARAF controls the MST2-Hippo pathway. Small GTPases 9 28281933
2016 MST2 phosphorylation at serine 385 in mitosis inhibits its tumor suppressing activity. Cellular signalling 9 27566175
2010 Mammalian MST2 kinase and human Salvador activate and reduce estrogen receptor alpha in the absence of ligand. Journal of molecular medicine (Berlin, Germany) 9 21104395
2025 STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis. Molecular cancer 8 40604818
2023 The TRIM69-MST2 signaling axis regulates centrosome dynamics and chromosome segregation. Nucleic acids research 8 37739411
2019 MST2 kinase regulates osteoblast differentiation by phosphorylating and inhibiting Runx2 in C2C12 cells. Biochemical and biophysical research communications 8 30910359
2022 Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma. Life science alliance 7 36038253
2016 Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process. Neurobiology of aging 7 27552481
2024 STK3 higher expression association with clinical characteristics in intrinsic subtypes of breast cancer invasive ductal carcinoma patients. Breast cancer research and treatment 6 38592540
2022 Valproic acid regulates MIEF1 through MST2-HIPPO to suppress breast cancer growth. Life sciences 6 36126724
2006 Characterization of the Ste20-like kinase Krs1 of Dictyostelium discoideum. European journal of cell biology 6 16842885
2022 Extracellular matrix stiffness regulates degradation of MST2 via SCF βTrCP. Biochimica et biophysica acta. General subjects 5 36044955
2022 Effect of Inactivation of Mst1 and Mst2 in the Mouse Adrenal Cortex. Journal of the Endocrine Society 5 36405866
2021 Dioscin inhibits SCC15 cell proliferation via the RASSF1A/MST2/YAP axis. Molecular medicine reports 5 33786612
2025 Dual inhibition of Mst1 and Mst2 exacerbates cardiac dysfunction during pressure overload stress in mice. Journal of molecular and cellular cardiology 4 39892959
2024 Toxoplasma gondii induces MST2 phosphorylation mediating the activation of hippo signaling pathway to promote apoptosis and lung tissue damage. iScience 4 39640582
2021 Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis. Journal of oncology 4 34557228
2021 Molecular and functional characterization of MST2 in grass carp during bacterial infection. Fish & shellfish immunology 4 34560286
2024 Association Study between SNPs in MST1 and MST2 and H. pylori Infection as well as Noncardia Gastric Carcinogenesis. Digestive diseases (Basel, Switzerland) 3 38295774
2024 STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma. Cellular oncology (Dordrecht, Netherlands) 3 38436783
2024 Role of MST2/YAP1 signaling pathway in retinal cells apoptosis and diabetic retinopathy. Toxicology and applied pharmacology 3 38447873
2017 The Kinase STK3 Interacts with the Viral Structural Protein VP1 and Inhibits Foot-and-Mouth Disease Virus Replication. BioMed research international 3 29226127
2015 Low pH-driven folding of WW45-SARAH domain leads to stabilization of the WW45-Mst2 complex. Journal of biochemistry 3 25814670
2023 Targeting the Divergent Roles of STK3 Inhibits Breast Cancer Cell Growth and Opposes Doxorubicin-Induced Cardiotoxicity In Vitro. Cancers 2 37345153
2021 STK3-ALK, a Novel ALK Rearrangement in Non-Small Cell Lung Cancer With Sensitivity to Tyrosine Kinase Inhibitors: A Case Report. Frontiers in oncology 2 34490099
2011 Crystallization and preliminary X-ray crystallographic study of the human MST2 SARAH domain. Acta crystallographica. Section F, Structural biology and crystallization communications 2 22102242