Affinage

STK3

Serine/threonine-protein kinase 24 · UniProt Q9Y6E0

Length
443 aa
Mass
49.3 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STK3 (MST2) is a stress-responsive Ste20-related serine/threonine kinase and the core kinase of the mammalian Hippo tumor-suppressor pathway, activated by apoptotic and stress stimuli rather than mitogens (PMID:8816758). Its activity depends on trans-autophosphorylation at Thr180 within the activation loop, a reaction triggered whenever adjacent kinase domains are brought into proximity—by SARAH-domain-mediated antiparallel homodimerization, membrane recruitment, or SAV1 (hWW45/Salvador) complex formation—so that no single dedicated assembly is required for activation (PMID:12554736, PMID:23972470, PMID:24468289, PMID:32994222). Once active, STK3 propagates Hippo signaling by phosphorylating the adaptor MOBKL1A/B (MOB1) at Thr74 and the downstream kinases LATS1 (S909/T1079) and NDR1, which in turn inactivate the transcriptional coactivator YAP via Ser127 phosphorylation, suppressing YAP/TAZ-driven proliferation and promoting apoptosis (PMID:15688006, PMID:18328708, PMID:18640976, PMID:18362890, PMID:19878874). This module enforces tumor suppression in vivo, as combined Mst1/Mst2 loss in liver causes loss of YAP Ser127 phosphorylation and hepatocellular carcinoma (PMID:19878874). STK3 activation is gated by an extensive regulatory network: it is held inactive by Raf-1 and A-Raf (which block dimerization and sequester the kinase) (PMID:15618521, PMID:20145135, PMID:26891695), by Akt phosphorylation at T117/T384 that drives Raf-1 binding and blocks homodimerization (PMID:20086174, PMID:20231902), by CDK1 (S385), by PRMT5 methylation of R461/R467 in the SARAH domain, and by SCFβTrCP-mediated degradation (PMID:27566175, PMID:37905571, PMID:36044955); it is positively regulated by RASSF1A, which protects activation-loop phosphorylation from PP2A and disrupts the inhibitory Raf-1 complex, by RASSF2 stabilization, by c-Abl phosphorylation at Y81, and by TRIM21 K63-ubiquitination at K473 (PMID:21199877, PMID:17889669, PMID:19525978, PMID:22590567, PMID:37354905). The K-Ras–RASSF1A–MST2–LATS1 axis couples Ras signaling kinetics to an apoptotic, p53-stabilizing output (PMID:22195963, PMID:23459937, PMID:24929361). Beyond canonical Hippo signaling, STK3 phosphorylates LC3 at Thr50 to enable autophagosome–lysosome fusion and bacterial clearance (PMID:25544559), phosphorylates histone H2B at Ser14 in nucleoli to shut down rDNA transcription after DNA damage (PMID:29789391), regulates Rac/RhoA GTPase signaling through Mob1–Dock8 to drive thymocyte and Treg migration and TLR-triggered antibacterial ROS production (PMID:22412158, PMID:26414765, PMID:30413360), and controls mitophagy via the receptor BNIP3 in adipocytes (PMID:33758424). The small-molecule inhibitor XMU-MP-1 confirms these activities pharmacologically and activates YAP to promote tissue repair (PMID:27535619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1996 Medium

    Established STK3 as a kinase activated by stress and apoptotic stimuli but not mitogens, defining its biological niche before any pathway context existed.

    Evidence Protein purification, cloning, and kinase activity assays

    PMID:8816758

    Open questions at the time
    • No substrates or upstream regulators identified
    • Activation mechanism unknown
  2. 1998 Medium

    Identified TTF-1 as the first substrate of this kinase class, providing initial evidence that STK3 directly phosphorylates a defined cellular target.

    Evidence In-gel and in vitro kinase assays with in vivo phosphosite mapping in rat ortholog

    PMID:9430685

    Open questions at the time
    • Physiological pathway linking STK3 to TTF-1 not established
    • Single substrate without broader signaling context
  3. 2003 High

    Defined the core activation mechanism—trans-autophosphorylation at Thr180—and showed caspase cleavage generates a dephosphorylation-resistant constitutively active form, linking activation to apoptosis.

    Evidence Mutagenesis, in vitro kinase and phosphatase assays, truncation mutants in cells

    PMID:12554736

    Open questions at the time
    • What drives the initial dimerization in cells not yet defined
    • Downstream effectors of cleaved form unknown
  4. 2004 High

    Placed STK3 downstream of Raf-1 in an apoptosis-suppressive pathway, revealing a kinase-independent inhibitory mechanism acting on dimerization.

    Evidence Proteomics, reciprocal Co-IP, siRNA, Raf-1-/- genetic epistasis

    PMID:15618521

    Open questions at the time
    • How RASSF proteins relieve this inhibition not yet shown
    • Structural basis of Raf-1 block undefined
  5. 2005 High

    Connected STK3 to the Hippo core by showing it phosphorylates and activates LATS1 and binds Salvador, establishing the kinase cascade architecture.

    Evidence In vitro kinase assay, MS phosphosite mapping, deletion analysis, Co-IP

    PMID:15688006 PMID:16930133

    Open questions at the time
    • Role of YAP as terminal effector not yet linked
    • In vivo relevance of LATS activation not tested
  6. 2008 High

    Defined MOB1 (Thr74) phosphorylation as the adaptor step enabling LATS1/NDR1 activation and showed the module restrains cell-cycle progression, completing the kinase relay logic.

    Evidence In vitro and cellular kinase assays, Co-IP, dominant-negative replacement, cell cycle and NDR1 activation assays

    PMID:18328708 PMID:18362890 PMID:18640976

    Open questions at the time
    • Whether MOB1 phosphorylation is the sole route to LATS activation unclear
    • Mitotic versus interphase roles not fully separated
  7. 2007 High

    Showed RASSF1A relieves Raf-1 inhibition to drive a proapoptotic MST2–LATS1–YAP–p73 axis, establishing how upstream signals switch the pathway toward apoptosis.

    Evidence Co-IP, siRNA, epistasis, reporter and apoptosis assays

    PMID:17889669

    Open questions at the time
    • How RASSF1A physically displaces Raf-1 not resolved
    • Tissue specificity of p73 versus YAP outputs unclear
  8. 2009 High

    Validated STK3 as a bona fide tumor suppressor in vivo and identified RASSF2 as a stabilizing partner, distinguishing context-dependent (liver) effector usage.

    Evidence Conditional knockout mice, phospho-specific blotting, endogenous Co-IP, localization and stability assays

    PMID:19525978 PMID:19878874

    Open questions at the time
    • Identity of the liver intermediary kinase distinct from LATS unknown
    • Mechanism of RASSF2-mediated stabilization undefined
  9. 2010 High

    Mapped the inhibitory inputs Akt (T117/T384) and A-Raf, showing how mitogenic and oncogenic signaling restrain STK3 proapoptotic activity.

    Evidence In vitro kinase assays, mutagenesis, Co-IP, Ras effector epistasis, apoptosis assays

    PMID:20086174 PMID:20145135 PMID:20231902

    Open questions at the time
    • Quantitative balance between activating and inhibitory inputs unclear
    • Whether these regulators act simultaneously not resolved
  10. 2011 High

    Established that RASSF1A protects STK3 activation-loop phosphorylation from PP2A and that mutant K-Ras engages this axis to stabilize p53, linking Ras mutation status to apoptotic output.

    Evidence PP2A dephosphorylation assays, knockdowns, Co-IP, Ras effector epistasis, apoptosis assays

    PMID:21199877 PMID:22195963

    Open questions at the time
    • How wild-type versus mutant K-Ras diverge mechanistically only partly defined
    • PP2A targeting specificity not fully mapped
  11. 2012 High

    Revealed a non-Hippo function: STK3-phosphorylated Mob1 activates the Rac-GEF Dock8 to drive GTPase signaling and lymphocyte migration, broadening STK3 into cytoskeletal regulation.

    Evidence Conditional double-knockout mice, Co-IP, GTP-loading and migration assays

    PMID:22412158

    Open questions at the time
    • How the same Mob1 phosphorylation switches between LATS and Dock8 outputs unclear
    • Direct STK3-Dock8 contact not defined
  12. 2013 High

    Provided structural proof that SARAH-mediated homodimerization enables trans-autophosphorylation and that RASSF5 binding has temporally dual roles, resolving the activation switch at atomic resolution.

    Evidence X-ray crystallography of kinase and SARAH-RASSF5 complexes, autophosphorylation assays, mutagenesis; plus Co-IP/AKT epistasis of Ras kinetics

    PMID:23459937 PMID:23972470

    Open questions at the time
    • How membrane recruitment substitutes for homodimerization not addressed here
    • Dynamics of dimer-to-monomer transitions unresolved
  13. 2014 High

    Expanded STK3 substrate repertoire (LC3 Thr50 for autophagy, H2B Ser14 for rDNA shutdown) and defined SARAH homodimer interface, c-Abl Y81 activation, and Raf-1 crosstalk circuitry, showing STK3 acts well beyond canonical Hippo.

    Evidence Crystallography, in vitro kinase assays, mutagenesis, autophagy/bacterial clearance and ChIP assays, mathematical modeling

    PMID:22590567 PMID:24468289 PMID:24929361 PMID:25544559 PMID:29789391

    Open questions at the time
    • Whether autophagy and Hippo functions are mechanistically separable unclear
    • Coordination among multiple substrate programs undefined
  14. 2015 High

    Showed STK3 activates Rac to assemble the TRAF6–ECSIT complex and recruit mitochondria to phagosomes, establishing a role in innate antibacterial ROS production.

    Evidence Conditional knockout mice, Co-IP, Rac GTP-loading, mitochondrial imaging, ROS and killing assays

    PMID:26414765

    Open questions at the time
    • Direct STK3 substrate in this axis not defined
    • Relationship to Mob1-Dock8 module unclear
  15. 2016 High

    Layered additional regulation—CDK1 mitotic phosphorylation, ERK-dependent inactive Mst1/Mst2 heterodimers, A-Raf subcellular relocalization, and the XMU-MP-1 inhibitor—refining how STK3 activity is tuned spatially and temporally.

    Evidence In vitro kinase assays, mutagenesis, Co-IP, fractionation, co-crystal structure, in vivo pharmacology

    PMID:26891695 PMID:27238285 PMID:27535619 PMID:27566175

    Open questions at the time
    • Functional weight of heterodimerization in vivo unclear
    • How CDK1 site affects non-Hippo functions untested
  16. 2018 High

    Extended the cytoskeletal-migration role to Treg cells via a DOCK8–LRCH module amplifying IL-2–STAT5 signaling, reinforcing STK3 control of immune cell positioning.

    Evidence Conditional knockout, unbiased Co-IP-MS, phospho-STAT5, migration and Rac assays

    PMID:30413360

    Open questions at the time
    • Direct kinase substrate in STAT5 amplification not defined
    • Mst1 versus Mst2 specific contributions unresolved
  17. 2020 High

    Unified the activation mechanism by demonstrating that kinase-domain proximity alone—via homodimerization, membrane recruitment, or SAV1—is sufficient to trigger autophosphorylation, with no dedicated assembly required.

    Evidence Chemically induced dimerization, single-molecule pulldown, in vitro and cell-based autophosphorylation

    PMID:32994222

    Open questions at the time
    • How distinct upstream events select downstream output not addressed
    • Endogenous trigger frequency in vivo unknown
  18. 2021 High

    Established STK3 control of mitophagy via the receptor BNIP3 in adipocytes, defining a metabolic function in mitochondrial quality control.

    Evidence Conditional knockout mice, Co-IP, BNIP3 phosphorylation/dimerization and mitochondrial function assays

    PMID:33758424

    Open questions at the time
    • Whether BNIP3 is a direct STK3 substrate not firmly established
    • Link to canonical Hippo signaling in adipocytes unclear
  19. 2022 Medium

    Identified opposing ubiquitin-system regulators—TRIM21 K63-ubiquitination (K473) activating, SCFβTrCP degradation (ECM-stiffness-driven) inactivating—showing post-translational and mechanical control of STK3 abundance and activity.

    Evidence Co-IP, mutagenesis, in vitro ubiquitination, proteasome inhibition, organoid and MD simulation

    PMID:36044955 PMID:37354905

    Open questions at the time
    • Reciprocal validation of ubiquitin marks limited to single labs
    • Interplay between the two ligases not tested
  20. 2023 High

    Defined PRMT5 arginine methylation (R461/R467) of the SARAH domain as a homodimerization-blocking off-switch, and TRIM69 as a spatial regulator coupling STK3 to PLK1 at centrosomes, broadening regulatory and mitotic functions.

    Evidence In vitro methylation/kinase/dimerization assays, mutagenesis, Co-IP, localization, centrosome phenotype, in vivo xenograft

    PMID:37739411 PMID:37905571

    Open questions at the time
    • Whether methylation and phosphorylation compete on the same SARAH surface unclear
    • TRIM69-S15/PLK1 axis confirmed by single lab only
  21. 2024 Medium

    Added context-specific substrates—GSK-3β (activating Wnt/β-catenin in a YAP1 feedback loop) and FOXO1 Ser212 (driving tumor-suppressive transcription)—illustrating STK3 outputs that diverge from canonical YAP suppression.

    Evidence Co-IP, in vitro kinase, ChIP, knockout mice, IF, xenograft assays

    PMID:38436783 PMID:40604818

    Open questions at the time
    • Apparent context-dependent oncogenic versus suppressive roles unreconciled
    • Single-lab findings without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How divergent upstream activating events and the diverse substrate repertoire are selected to produce specific cellular outputs (apoptosis, autophagy, migration, mitophagy, transcription) within a single cell remains unresolved.
  • No unifying model linking activation context to output choice
  • Quantitative integration of competing regulators not established
  • Tissue-specific substrate selection mechanisms undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 5 GO:0042393 histone binding 1
Localization
GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1640170 Cell Cycle 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2
Partners
AKT1LATS1MOB1RAF1RASSF1ARASSF5SAV1TRIM21
Complex memberships
MOB1–MST2–NDR1 complexMST2–Raf-1 inhibitory complexMST2–SAV1 (hWW45/Salvador)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 STK3 (KRS1/MST2) is a Ste20-related serine/threonine kinase that is activated by a subset of stress conditions and apoptosis-inducing agents but not by mitogenic stimuli, establishing it as a stress-responsive kinase. Protein purification, cloning, and kinase activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 8816758
1998 Rat MST2 (STK3 ortholog) phosphorylates thyroid transcription factor-1 (TTF-1) at the same residues previously identified as major in vivo phosphorylation sites, identifying TTF-1 as the first substrate of this kinase class. In-gel kinase assay, cloning, in vitro kinase assay, in vivo phosphorylation mapping The Journal of biological chemistry Medium 9430685
2003 MST2 (STK3) kinase activity depends on autophosphorylation at Thr180 via an intermolecular (trans) mechanism; caspase-3 cleaves MST2 generating a truncated form that is resistant to dephosphorylation by PP1 and PP2A, in contrast to full-length MST2 which is rapidly dephosphorylated, explaining constitutive activation of the truncated form during apoptosis. Site-directed mutagenesis, in vitro kinase assays, phosphatase treatment, cell transfection with truncation mutants The Journal of biological chemistry High 12554736
2004 Raf-1 suppresses MST2 (STK3) activation by preventing its dimerization and activation-loop phosphorylation independently of Raf-1 kinase activity; depletion of MST2 from Raf-1-/- cells abrogates apoptosis hypersensitivity, placing MST2 downstream of Raf-1 in an apoptosis-suppressive pathway. Proteomic analysis of Raf-1 signaling complexes, Co-IP, siRNA knockdown, genetic epistasis (Raf-1-/- cells), overexpression Science High 15618521
2005 MST2 (STK3) phosphorylates LATS1 at its activation loop (S909) and hydrophobic motif (T1079), activating LATS1 kinase activity; MST2 also directly interacts with hWW45 (Salvador ortholog) via their conserved domains. In vitro kinase assay, mass spectrometry phosphosite mapping, deletion analysis, Co-IP Oncogene High 15688006
2006 MST1 and MST2 (STK3) heterodimerize with hSav (hWW45/Salvador) via conserved C-terminal coiled-coil (SARAH) domains; this interaction leads to hSav phosphorylation by Mst kinases and stabilization of hSav protein, with stabilization requiring the Mst-hSav interaction but not necessarily phosphorylation. Co-IP, deletion mutagenesis, in vitro phosphorylation, co-expression abundance assays The FEBS journal Medium 16930133
2007 RASSF1A disrupts the inhibitory Raf-1–MST2 complex, enhancing MST2 interaction with LATS1; RASSF1A-activated LATS1 phosphorylates YAP1, releasing it to translocate to the nucleus and associate with p73, driving transcription of the proapoptotic gene PUMA. Co-IP, siRNA knockdown, epistasis analysis, reporter assays, apoptosis assays Molecular cell High 17889669
2008 MST1 and MST2 (STK3) phosphorylate MOBKL1A/MOBKL1B (Mats homologs) as preferred substrates in vitro and in cells during mitosis; MST1/2 activity increases during mitosis (especially in nocodazole arrest); MOBKL1A/B phosphorylation promotes their binding to LATS1 and enables LATS1 activation-loop phosphorylation; replacing endogenous MOBKL1A/B with non-phosphorylatable mutants accelerates cell proliferation through G1/S and mitotic exit. In vitro kinase assay, cell-based phosphorylation (okadaic acid/H2O2 treatment), Co-IP, dominant-negative replacement, cell cycle analysis Current biology High 18328708
2008 MST2 (STK3) cooperates with LATS1 kinase to phosphorylate YAP at Ser-127, requiring WW domains of YAP and PPxY motifs in LATS kinases; in HEK293 cells this Hippo pathway reconstitution is anti-apoptotic, partially rescuing cells from YAP2-induced apoptotic death; nuclear localization of YAP2 is negatively regulated by LATS1. Reconstitution in human cells, Co-IP with deletion/point mutants, subcellular fractionation/localization, apoptosis assays The Journal of biological chemistry Medium 18640976
2008 MST2 phosphorylates MOB1 at Thr74 in vitro; this phosphorylation is essential for forming the MOB1–MST2–NDR1 complex and for full activation of NDR1; MOB1 T74A mutant fails to enhance its interaction with NDR1 upon okadaic acid stimulation. In vitro kinase assay, site-directed mutagenesis (T74A, T181A), Co-IP, NDR1 activation assay Oncogene High 18362890
2009 MST2 (STK3) promotes MST2-dependent NDR1 activation and precise chromosome alignment at metaphase; depletion of MST2 or Fry or MOB2 causes mitotic chromosome misalignment; expression of active NDR1 rescues MST2-depletion misalignment; Fry acts as a scaffold binding NDR1, MOB2, and microtubules on the spindle. siRNA knockdown, live-cell imaging, rescue by active NDR1, biochemical interaction (Co-IP/pulldown) Current biology Medium 19327996
2009 In mouse liver, Mst1 and Mst2 are cleaved and constitutively activated; combined deficiency results in loss of inhibitory Ser127 phosphorylation of Yap1 and hepatocellular carcinoma; Mst1/2 inactivates Yap1 through an intermediary kinase distinct from Lats1/2 in the liver context. Conditional knockout mice, phospho-specific western blot, re-expression rescue in HCC cell lines Cancer cell High 19878874
2009 RASSF2 directly binds and stabilizes MST2 (STK3) protein at endogenous levels; RASSF2 co-localizes with MST2 in the cytoplasm (shifting MST2 from nuclear-alone); RASSF2 expression increases MST2 protein levels and protects MST2 from proteolytic degradation; RASSF2 itself is phosphorylated by co-immunoprecipitated MST1/2. Endogenous Co-IP, co-localization imaging, siRNA knockdown, immunoblotting for protein stability Oncogene Medium 19525978
2010 Akt phosphorylates MST2 at T117 and T384; these phosphorylations inhibit MST2 by (1) blocking its binding to RASSF1A, (2) promoting its association into the Raf-1 inhibitory complex, and (3) preventing MST2 homodimerization required for activation; Akt thus limits MST2 proapoptotic activity downstream of mitogens and oncogenic Ras. In vitro kinase assay, site-directed mutagenesis (T117A/T384A), Co-IP, epistasis with Ras effector domain mutants Cancer research High 20086174
2010 Akt phosphorylates MST2 at T117, leading to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation at Thr180, and kinase activity; IGF1-PI3K-Akt signaling suppresses DNA damage-induced MST2 activation. In vitro and in vivo labeling kinase assays, site-directed mutagenesis, immunoblotting PloS one Medium 20231902
2010 A-Raf prevents MST2-mediated apoptosis in cancer cells by sequestering and inactivating MST2; this requires hnRNP H-dependent A-Raf transcription; siRNA knockdown of hnRNP H or A-Raf results in MST2-dependent apoptosis. siRNA knockdown, Co-IP, apoptosis assays Cancer research Medium 20145135
2011 The tumor suppressor RASSF1A prevents PP2A-mediated dephosphorylation of MST1/2 at their activation-loop residues (Thr183/Thr180), maintaining MST2 in an activated, autophosphorylated state; RASSF1A also stabilizes MST2 protein. Dephosphorylation assays with PP2A, PP2A knockdown, RASSF1A depletion, phospho-specific western blot The Journal of biological chemistry High 21199877
2011 Mutant K-Ras directly binds RASSF1A to activate the apoptotic MST2–LATS1 pathway; activated LATS1 sequesters Mdm2 to stabilize p53 and drive apoptosis; wild-type K-Ras inhibits this pathway via AKT activation. Co-IP, siRNA knockdown, epistasis analysis with Ras effector domain mutants, apoptosis assays Molecular cell High 22195963
2012 Mst1 and Mst2 (STK3) control Rho GTPase activation (Rac1 and RhoA GTP charging) in SP thymocytes; when phosphorylated by Mst1/2, Mob1 binds and activates the Rac1 guanyl nucleotide exchanger Dock8; this pathway drives sphingosine-1-phosphate and CCL21-induced cell migration and thymic egress. Conditional double knockout mice, Co-IP, GTP-loading assays, migration assays, phospho-Mob1 blotting The Journal of experimental medicine High 22412158
2013 Crystal structure of human MST2 kinase domain alone and in complex with RASSF5 (SARAH domain) reveals that MST2 undergoes activation via trans-autophosphorylation at its activation loop, requiring SARAH domain-mediated homodimerization; RASSF5 binding disrupts MST2 homodimer, blocking autoactivation of unphosphorylated MST2 but not inhibiting already-activated MST2, revealing temporal context-dependent dual roles for RASSF5. X-ray crystallography, biochemical autophosphorylation assays, mutagenesis Structure High 23972470
2013 Chronic (not transient) K-Ras activation drives MST2–LATS1 complex formation and apoptosis; transient EGF-stimulated K-Ras activation prevents MST2–LATS1 complex formation in an AKT-dependent manner, demonstrating that activation kinetics determine pathway output. Co-IP, siRNA, AKT inhibition, overexpression of Ras exchange factors, apoptosis assays Molecular and cellular biology Medium 23459937
2014 c-Abl tyrosine kinase phosphorylates MST2 at the conserved site Y81 within the kinase domain; this phosphorylation disrupts MST2–Raf-1 interaction, enhances MST2 homodimerization and kinase activation, and induces neuronal cell death. In vitro kinase assay, site-directed mutagenesis (Y81F), Co-IP, cell death assay PloS one Medium 22590567
2014 Competing protein interactions coordinate Raf-1–MST2 crosstalk: Akt phosphorylation of MST2 and LATS1-feedback phosphorylation of Raf-1 Ser259 enable Raf-1 to suppress both MST2 and MEK signaling; mutation of Raf-1 Ser259 simultaneously drives apoptosis and proliferation; concomitant MST2 downregulation switches outcome to proliferation and transformation. Phosphorylation assays, Co-IP, mutagenesis, mathematical modeling validated by experiment, cell transformation assays Nature cell biology High 24929361
2014 STK3 (MST2) and STK4 (MST1) phosphorylate LC3 at threonine 50 (Thr50); loss of this phosphorylation blocks autophagosome–lysosome fusion and impairs intracellular bacterial clearance; constitutive phosphomimetic LC3-T50E reverses autophagy block in STK3/STK4-deficient cells. In vitro kinase assay, site-directed mutagenesis, autophagy flux assays, bacterial clearance assay, genetic rescue Molecular cell High 25544559
2014 Crystal structure of the MST2 SARAH domain shows it forms an antiparallel homodimeric coiled coil; structure-guided mutagenesis identified interface residues critical for homodimerization; these same mutations also impaired heterodimerization with RAPL (RASSF5); SARAH-mediated homodimerization and RAPL heterointeraction are both required for full MST2 activation and apoptotic functions in T cells. X-ray crystallography, site-directed mutagenesis, Co-IP, kinase activity assays, apoptosis assays Journal of structural biology High 24468289
2014 MST2 (STK3) kinase suppresses rDNA transcription in response to DNA damage by phosphorylating histone H2B at serine 14 (H2BS14p) in an ATM-dependent manner; MST2 localizes to nucleoli; H2BS14p marks transcriptionally inactive nucleolar chromatin and is necessary for rDNA transcriptional shutdown and genomic integrity maintenance. ChIP, immunofluorescence localization, siRNA knockdown, kinase assays, ATM inhibition The EMBO journal High 29789391
2015 Mst1 and Mst2 (STK3) activate the GTPase Rac to promote TLR-triggered assembly of the TRAF6–ECSIT complex, which recruits mitochondria to phagosomes for synergistic ROS production and bactericidal activity. Conditional knockout mice, Co-IP, Rac GTP-loading assays, mitochondria trafficking (imaging), ROS measurement, bacterial killing assays Nature immunology High 26414765
2016 XMU-MP-1 is a selective, reversible MST1/2 inhibitor confirmed by co-crystal structure; it blocks MST1/2 kinase activities, activates downstream YAP, and promotes tissue repair in mouse intestinal and liver injury models. Enzyme-based HTS, co-crystal structure, structure-activity relationship, in vivo pharmacology Science translational medicine High 27535619
2016 H-Ras promotes formation of inactive Mst1–Mst2 heterodimers via their SARAH domains in an ERK-dependent manner; Mst1/Mst2 heterodimers have much-reduced kinase activity compared to homodimers; cells lacking Mst1 (unable to form heterodimers) are resistant to H-Ras transformation and maintain active Hippo signaling. Co-IP, kinase activity assays comparing homo- vs heterodimers, ERK pathway inhibition, Mst1 knockout cells, transformation assays Current biology Medium 27238285
2016 CDK1 phosphorylates MST2 at serine 385 during mitosis in vitro and in vivo; this phosphorylation does not affect MST2 kinase activity or Hippo-YAP signaling, but phosphorylation-deficient MST2-S385A has higher activity in suppressing proliferation and tumorigenesis, establishing CDK1-mediated mitotic regulation of MST2 tumor suppression. In vitro CDK1 kinase assay, phospho-site mutagenesis (S385A), cell proliferation and anchorage-independent growth assays, in vivo xenograft Cellular signalling Medium 27566175
2016 A-Raf subcellular localization regulates MST2 activity: A-Raf at mitochondria (in proliferating/cancer cells) efficiently sequesters and inhibits MST2, while A-Raf relocated to the plasma membrane (during differentiation) loses its ability to inhibit MST2; this redistribution is regulated by the scaffold KSR2. Subcellular fractionation, live-cell imaging, siRNA knockdown of KSR2, apoptosis assays Cell death and differentiation Medium 26891695
2018 Mst1 and Mst2 amplify IL-2–STAT5 signaling in regulatory T cells by promoting STAT5 activation; Mst1 associates with the cytoskeletal DOCK8–LRCH module; Mst1 deficiency limits Treg cell migration and access to IL-2, and impairs Rac GTPase activity mediating STAT5 activation. Conditional knockout mice, quantitative proteomics (unbiased Co-IP-MS), phospho-STAT5 assays, migration assays, Rac activation assays Immunity High 30413360
2019 MST2 phosphorylates Runx2 at Ser339 and Ser370 (identified by mass spectrometry); MST2 interacts with Runx2 via SAV1's WW domain binding to a PY motif (aa 292–445) of Runx2; phosphorylation inhibits Runx2 transcriptional activity and osteoblast differentiation; phosphorylation-deficient double mutant (S339A/S370A) is resistant to MST2/SAV1-mediated inhibition. In vitro kinase assay, mass spectrometry phosphosite mapping, Co-IP domain mapping, reporter assay, differentiation assays, mutagenesis Biochemical and biophysical research communications Medium 30910359
2020 Increasing proximity of adjacent MST2 kinase domains—via SARAH domain homodimerization, membrane recruitment, or complex formation with SAV1—is sufficient to trigger MST2 autophosphorylation; a specific protein assembly is not required; multiple upstream activating events converge on this common molecular mechanism. Chemically induced dimerization, single-molecule pulldown, in vitro biochemistry, cell-based autophosphorylation assays The Journal of biological chemistry High 32994222
2021 STK3 and STK4 (MST2/MST1) suppress mitochondrial capacity and mitophagy in adipocytes; mechanistically, STK3/4 regulate phosphorylation and dimerization status of the mitophagy receptor BNIP3; genetic inactivation of Stk3/4 increases mitochondrial mass/function and stabilizes UCP1 in beige adipose tissue. Conditional knockout mice, Co-IP, BNIP3 phosphorylation/dimerization assays, mitochondrial function assays Nature metabolism High 33758424
2022 MST2 is ubiquitinated at K473 via K63-linkage by the E3 ligase TRIM21; this ubiquitination promotes MST2 homodimerization and enhances its kinase activity, leading to YAP inactivation and inhibition of EMT in colorectal cancer. Co-IP, site-directed mutagenesis (K473), in vitro ubiquitination assay, kinase activity assay, tumor organoid models Cell chemical biology Medium 37354905
2022 MST2 binds SCFβTrCP E3 ubiquitin ligase via a non-canonical degradation motif and is degraded via proteasomal proteolysis; stiffer extracellular matrix and integrin hyperactivation enhance MST2 degradation through integrin-linked kinase (ILK) and actomyosin stress fibers. Co-IP, siRNA knockdown of βTrCP, site-directed mutagenesis, proteasome inhibition, molecular dynamics simulation Biochimica et biophysica acta. General subjects Medium 36044955
2023 PRMT5 symmetrically di-methylates MST2 (STK3) at R461 and R467 in its SARAH domain, suppressing MST2 autophosphorylation and kinase activity by blocking homodimerization, thereby inactivating Hippo signaling in pancreatic cancer. In vitro methylation assay, site-directed mutagenesis (R461/R467), dimerization assays, kinase activity assays, Co-IP, in vivo xenograft with PRMT5 inhibitor The EMBO journal High 37905571
2023 TRIM69 binds MST2 directly, redistributes it to the perinuclear cytoskeleton, promotes MST2 association with PLK1, and stimulates MST2 phosphorylation at S15 (a PLK1 site critical for centrosome disjunction); TRIM69 ablation causes centrosome scattering and chromosome segregation defects. Co-IP, immunofluorescence localization, phospho-S15 western blot, siRNA knockdown with centrosome and mitosis phenotype readout Nucleic acids research Medium 37739411
2024 In gastric cancer, STK3 directly interacts with GSK-3β and phosphorylates it, promoting GSK-3β degradation and β-catenin nuclear accumulation, thereby activating Wnt/β-catenin signaling; STK3 is itself a transcriptional target of YAP1, creating a feedback loop. Co-IP, in vitro kinase assay, ChIP-qPCR, knockout mouse models, functional rescue assays, xenograft models Molecular cancer Medium 40604818
2024 STK3 (MST2) activation phosphorylates FOXO1 at Ser212, promoting its nuclear translocation and transcriptional activation of TP53INP1 and P21 to inhibit ESCC cell proliferation and migration; cellular ROS activates STK3 autophosphorylation in ESCC cells. Co-IP, immunofluorescence, ChIP, western blot, siRNA, xenograft models Cellular oncology Medium 38436783
2016 STK3 (MST2) interacts with apoptosis-inducing factor (AIF); AIF interaction enhances STK3 phosphorylation at Thr180, suggesting AIF is a positive regulator of STK3 activity. Co-IP, in vitro phosphorylation assay PloS one Low 24992339

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 796 19878874
2005 The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 503 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 474 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 405 22042863
2008 MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Current biology : CB 359 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 332 27535619
2008 Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). The Journal of biological chemistry 311 18640976
2004 Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science (New York, N.Y.) 268 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 228 16930133
2015 Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nature immunology 212 26414765
2014 Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Molecular cell 159 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 141 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) 125 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 99 30413360
2009 MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes. Current biology : CB 96 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 81 23985272
2016 MST1/MST2 Protein Kinases: Regulation and Physiologic Roles. Biochemistry 76 27618557
2009 RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene 70 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 64 24766643
2003 Regulation of mammalian STE20-like kinase 2 (MST2) by protein phosphorylation/dephosphorylation and proteolysis. The Journal of biological chemistry 59 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 39 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
2023 TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell chemical biology 34 37354905
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
2014 The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy. The Journal of biological chemistry 33 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 30 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
2023 MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression. The EMBO journal 26 37905571
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
2020 Hippo kinases MST1 and MST2 control the differentiation of the epididymal initial segment via the MEK-ERK pathway. Cell death and differentiation 26 32332916
2016 H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization. Current biology : CB 26 27238285
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 21 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
2015 LC3 is a novel substrate for the mammalian Hippo kinases, STK3/STK4. Autophagy 16 25996575
2020 MST2 silencing induces apoptosis and inhibits tumor growth for estrogen receptor alpha-positive MCF-7 breast cancer. Toxicology and applied pharmacology 15 33007383
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
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
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 11 40604818
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
2023 The TRIM69-MST2 signaling axis regulates centrosome dynamics and chromosome segregation. Nucleic acids research 10 37739411
2022 Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner. Cell death & disease 10 35941108
2017 Spatial regulation of ARAF controls the MST2-Hippo pathway. Small GTPases 10 28281933
2014 AIF downregulation and its interaction with STK3 in renal cell carcinoma. PloS one 10 24992339
2019 MST2 kinase regulates osteoblast differentiation by phosphorylating and inhibiting Runx2 in C2C12 cells. Biochemical and biophysical research communications 9 30910359
2018 STK3 is a therapeutic target for a subset of acute myeloid leukemias. Oncotarget 9 29876001
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
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 Extracellular matrix stiffness regulates degradation of MST2 via SCF βTrCP. Biochimica et biophysica acta. General subjects 6 36044955
2022 Valproic acid regulates MIEF1 through MST2-HIPPO to suppress breast cancer growth. Life sciences 6 36126724
2022 Effect of Inactivation of Mst1 and Mst2 in the Mouse Adrenal Cortex. Journal of the Endocrine Society 6 36405866
2006 Characterization of the Ste20-like kinase Krs1 of Dictyostelium discoideum. European journal of cell biology 6 16842885
2024 Toxoplasma gondii induces MST2 phosphorylation mediating the activation of hippo signaling pathway to promote apoptosis and lung tissue damage. iScience 5 39640582
2021 Dioscin inhibits SCC15 cell proliferation via the RASSF1A/MST2/YAP axis. Molecular medicine reports 5 33786612
2021 Molecular and functional characterization of MST2 in grass carp during bacterial infection. Fish & shellfish immunology 5 34560286
2025 Dual inhibition of Mst1 and Mst2 exacerbates cardiac dysfunction during pressure overload stress in mice. Journal of molecular and cellular cardiology 4 39892959
2021 Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis. Journal of oncology 4 34557228
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
2025 Molybdenum disulfide induces growth inhibition and autophagy-dependent hepatocyte cell death through directly binding and regulating the activity of MST2. Materials today. Bio 2 41142426
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

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