| 2001 |
MST4 is a novel Ste20-related serine/threonine kinase with an N-terminal kinase domain and unique C-terminal regulatory domain; wild-type but not kinase-dead MST4 phosphorylates myelin basic protein in vitro, and MST4 activates ERK via a Ras/Raf-1 independent pathway through MEK1. |
In vitro kinase assay with myelin basic protein substrate; dominant-negative MEK1 overexpression and PD98059 treatment; dominant-negative Ras/Raf-1 epistasis in transfected cells |
Oncogene |
High |
11641781
|
| 2001 |
MST4 requires both its kinase and C-terminal regulatory domains for full kinase activation; an alternatively spliced isoform MST4a (lacking kinase subdomains IX–XI) may act as a dominant-negative regulator; MST4 was cloned via yeast two-hybrid interaction with the catalytic domain of Raf. |
Domain deletion analysis; Northern blot; yeast two-hybrid screening; fluorescence in situ hybridization for chromosomal localization to Xq26 |
The Journal of biological chemistry |
Medium |
11306563
|
| 2007 |
PDCD10 (CCM3) directly interacts with MST4 (confirmed by co-immunoprecipitation and colocalization), increases MST4 kinase activity in vitro, and acts as a regulatory adaptor for MST4-mediated ERK pathway activation promoting cell proliferation and transformation. |
Yeast two-hybrid screening; co-immunoprecipitation; colocalization assays; in vitro kinase assay; siRNA knockdown with ERK activity readout |
Molecular biology of the cell |
High |
17360971
|
| 2009 |
MST4 acts downstream of the LKB1/STRAD/MO25 polarization complex; Mo25α directly interacts with MST4, and upon LKB1 activation, MST4 translocates from the Golgi to the subapical membrane compartment. MST4 phosphorylates the regulatory T567 residue of Ezrin, which is essential for brush border formation; inhibition of MST4 blocks brush border formation without affecting lateral junction formation. |
Protein interaction assays; live-cell imaging/subcellular fractionation; in vitro kinase assay for Ezrin T567 phosphorylation; dominant-negative MST4 inhibition with morphological readout |
Developmental cell |
High |
19386264
|
| 2011 |
MO25α and MO25β bind to MST4 (and MST3/YSK1) in a manner similar to STRAD binding, stimulating MST4 kinase activity approximately 3–4-fold; MO25 is thus a master activator of multiple STE20-family kinases beyond LKB1 regulation. |
Biochemical binding assays; in vitro kinase activity measurements; siRNA knockdown of MO25 in mammalian cells |
The EMBO journal |
High |
21423148
|
| 2013 |
Crystal structure of MST4 in complex with MO25 reveals that MO25 binding rotates the αC helix of MST4 into an active conformation. The MST4 kinase domain forms a specific homodimer required for trans-autophosphorylation. Interface mutations disrupting either MST4-MO25 interaction or kinase-domain homodimerization impair MST4 kinase activation and function. MO25-stimulated MST4 promotes apoptosis in HEK293T cells. |
X-ray crystallography; site-directed mutagenesis of interface residues; in vitro kinase assays; cell-based apoptosis assay |
Structure |
High |
23434407
|
| 2015 |
MST4 directly phosphorylates TRAF6 at Thr463 and Thr486 to prevent TRAF6 oligomerization and autoubiquitination, thereby limiting LPS-induced inflammatory cytokine production. Mutation of TRAF6 at these sites abrogates MST4-mediated inhibition. MST4 knockdown exacerbates septic shock in mice, an effect rescued by heterozygous Traf6 deletion. |
In vitro kinase assay; site-directed mutagenesis of TRAF6 phospho-acceptor sites; co-immunoprecipitation; genetic epistasis in Traf6-/- fibroblasts; in vivo MST4 knockdown mouse model |
Nature immunology |
High |
25642822
|
| 2015 |
PKA phosphorylates MST4 at Thr178, activating its kinase activity. Activated MST4 then phosphorylates Ezrin at Thr567 (in addition to PKA phosphorylating Ezrin at Ser66), and this PKA-MST4-Ezrin signaling cascade is required for histamine-elicited acid secretion and apical membrane reorganization in gastric parietal cells. Non-phosphorylatable MST4 or Ezrin mutants block proton pump translocation. |
In vitro kinase assay; site-directed mutagenesis; overexpression of phospho-deficient mutants; gastric acid secretion functional assay; immunofluorescence of parietal cell membranes |
The Journal of biological chemistry |
High |
26405038
|
| 2015 |
The MST4 crystal structure ATP-binding site was used for virtual docking to identify hesperadin as a potent nanomolar inhibitor of MST4 kinase activity; hesperadin blocks MST4-mediated protection from hypoxia-induced apoptosis and proliferation in pituitary gonadotrope cells. |
Structure-based virtual screening; TR-FRET in vitro recombinant kinase assay; cell-based apoptosis and proliferation assays with hypoxia model |
Molecular cancer therapeutics |
Medium |
26721946
|
| 2017 |
MST4 (STK26) phosphorylates ATG4B at Ser383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B suppresses autophagy and tumorigenicity of glioblastoma cells. Radiation induces MST4 expression and ATG4B phosphorylation. |
In vitro kinase assay identifying specific phosphorylation site; genetic knockdown/inhibitor studies with autophagic flux readout; in vivo intracranial xenograft model with radiotherapy combination |
Cancer cell |
High |
29232556
|
| 2017 |
MST4 phosphorylates ACAP4 (an ARF6 GTPase-activating protein) at Thr545, which is essential for apical membrane reorganization and H,K-ATPase proton pump translocation during histamine-elicited gastric acid secretion. Phosphorylation of Thr545 enables ACAP4 interaction with Ezrin, and MST4-ACAP4 interaction is promoted by histamine stimulation. |
In vitro kinase assay; mass spectrometric phosphorylation site mapping; co-immunoprecipitation; overexpression of non-phosphorylatable ACAP4 mutant; gastric acid secretion functional assay |
The Journal of biological chemistry |
High |
28808054
|
| 2018 |
MST4 forms a phosphorylation-dependent complex with MOB4; the MST4-MOB4 complex has an overall structure resembling the MST1-MOB1 complex but exhibits opposite (pro-oncogenic) biological function. MST4-MOB4 can disrupt the MST1-MOB1 complex through alternative pairing due to divergent evolution of interface residues, thereby increasing YAP activity. |
Co-immunoprecipitation; structural analysis; cell growth and migration assays with PANC-1 cells; competitive binding experiments |
The Journal of biological chemistry |
Medium |
30072378
|
| 2020 |
MST4 directly phosphorylates YAP at Thr83, which blocks YAP binding to importin α, leading to YAP cytoplasmic retention and inactivation. This MST4-YAP axis is a noncanonical Hippo pathway; T83E YAP mutation mimicking MST4 phosphorylation restrains both wild-type YAP and its S127A mutant activity. MST4 depletion in mice promotes gastric tumorigenesis with YAP hyperactivation. |
In vitro kinase assay; site-directed mutagenesis (T83E phospho-mimetic); importin α binding assay; MST4 knockout mouse model with tumorigenesis readout |
The Journal of experimental medicine |
High |
32271880
|
| 2021 |
MST4 directly phosphorylates β-catenin at Thr40, blocking its Ser33 phosphorylation by GSK3β and thereby preventing β-TrCP-mediated degradation and leading to β-catenin accumulation and full activation. This MST4-pβ-cateninThr40 axis is required for intestinal stem cell homeostasis; mice with MST4T178E (constitutively active) or β-cateninT40D mutations show excess ISCs/CSCs and exacerbated CRC. |
In vitro kinase assay; phospho-site mutagenesis (T40D phospho-mimetic); GSK3β phosphorylation competition assay; β-TrCP binding assay; MST4 depletion with ISC phenotype readout; in vivo mouse models |
Advanced science |
High |
34240584
|
| 2022 |
MST4 negatively regulates type I interferon production by competing with TRAF3 for binding to the 360-540 domain of MAVS, and by facilitating Smurf1-MAVS interaction, thereby promoting K48-linked ubiquitination and proteasomal degradation of MAVS. |
Co-immunoprecipitation; immunofluorescence colocalization; ELISA for IFN-β; RT-PCR for IFN-stimulated genes; siRNA knockdown and overexpression in virus-infected cells |
Cell communication and signaling |
Medium |
35820905
|
| 2023 |
MST4 directly phosphorylates STAT1, and this phosphorylation is essential for M1 polarization of macrophages; MST4 knockdown directly inhibits STAT1 phosphorylation, reduces M1 macrophage markers and cytokines, and impairs phagocytosis. Macrophage-specific Mst4 knockout in mice attenuates ITP pathology. |
Co-immunoprecipitation; mass spectrometry; phosphoproteomics; macrophage-specific Mst4 knockout mouse model; immunofluorescence; RNA-seq |
Cellular & molecular immunology |
Medium |
37833401
|
| 2023 |
MST3 and MST4 interact with GOLGA2 (GM130) and STRIPAK complex components in hepatocytes; silencing of MST4 markedly suppressed tumorigenesis and identified lower STAT3 signaling activation in MST3/MST4-deficient HCC cells. |
Co-immunoprecipitation identifying GOLGA2 and STRIPAK as binding partners; siRNA silencing with proliferation/migration/invasion/EMT readouts; public dataset analysis |
FASEB journal |
Medium |
37490000
|
| 2024 |
MST4 associates with STRIPAK complex components in cardiomyocytes and localizes to the intercalated disc, interacting with intercalated disc proteins. MST4 overexpression induces cardiomyocyte hypertrophy, increases sarcomeric fractional shortening (contractility), and inhibits apoptosis (reduced cleaved caspase3, caspase7, and PARP1). Phosphoproteomics identified novel MST4 target candidates at the intercalated disc. |
Co-immunoprecipitation with STRIPAK components; immunofluorescence localization to intercalated disc; overexpression in adult rat cardiomyocytes with contractility and apoptosis readouts; phosphoproteomics |
The Journal of biological chemistry |
Medium |
38579991
|
| 2025 |
MST4 phosphorylates ALKBH5 at Ser64 and Ser69, which increases ALKBH5 interaction with the deubiquitinase USP14, promoting ALKBH5 deubiquitylation and stabilization (preventing HECW2-mediated K48-linked ubiquitination). This MST4-USP14-ALKBH5 axis enhances GBM stem cell radioresistance and homologous recombination repair. |
Mass spectrometry; co-immunoprecipitation; phospho-site mutagenesis; ubiquitination assay; shRNA knockdown with radioresistance and xenograft readouts |
Theranostics |
Medium |
39990235
|
| 2025 |
LIMK2 phosphorylates MST4 at Thr178, activating its kinase function; activated MST4 then binds and phosphorylates nucleophosmin 1 (NPM1) at Thr95, a modification essential for centrosome clustering and tumor cell proliferation. |
In vitro kinase assay; site-directed mutagenesis; co-immunoprecipitation; NPM1 siRNA knockdown with centrosome clustering readout; in vivo xenograft and 4NQO carcinogenesis mouse models |
Oncogene |
High |
40775397
|
| 2026 |
MST4 directly interacts with p53 protein and competes with MDM2 to prevent K48-linked ubiquitination and degradation of both wild-type and gain-of-function mutant p53, thereby stabilizing p53 in a kinase-independent manner. |
CRISPR-generated MST4 knockout cell lines; co-immunoprecipitation; ubiquitination assay; MDM2 competition assay; xenograft model |
Oncogene |
Medium |
42204266
|
| 2026 |
MST4 forms a phosphorylation-dependent complex with 14-3-3ζ, leading to YAP activation and enhanced pancreatic cancer cell migration; X-ray crystallographic structural analysis revealed the MST4–14-3-3ζ complex interface. Peptide inhibitors disrupting this interaction suppressed YAP activation and tumor growth in vitro and in vivo. |
BioID proximity labeling; microscale thermophoresis; isothermal titration calorimetry; X-ray crystallography; cell migration assay; xenograft mouse model |
Biology direct |
High |
41981454
|
| 2025 |
MST4 (STK26) interacts with p50ATF6 and enhances its protein stabilization, activating the ATF6 unfolded protein response signaling branch to promote colorectal cancer cell growth and migration; MST4's oncogenic function depends on ATF6 as shown by ATF6 inhibitor reversal. |
Co-immunoprecipitation; luciferase reporter assay for ATF6 pathway activation; transcriptome sequencing; tumor phenotype assays; in vivo hesperadin (STK26 inhibitor) treatment |
International journal of molecular sciences |
Medium |
40869379
|
| 2025 |
MST4 promotes TRAF6 autoubiquitination through phosphorylation in osteoclasts, a critical event for osteoclast activation. MST4 knockdown reduced osteoclast differentiation and bone resorption; MST4 overexpression enhanced these processes. In vivo ovariectomized mouse models corroborated these findings. |
In vitro osteoclast differentiation assay; siRNA knockdown and overexpression; bone resorption assay; ubiquitination assay; ovariectomized mouse model |
Journal of pharmaceutical analysis |
Medium |
41940169
|
| 2021 |
MST4 protein is predominantly associated with intracellular lipid droplets in human and rodent hepatocytes; MST4 silencing attenuates lipid accumulation by stimulating β-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipogenesis; MST4 overexpression has the opposite effects, also affecting oxidative/ER stress. |
Subcellular fractionation/immunofluorescence identifying lipid droplet localization; siRNA silencing and OE with metabolic flux assays (β-oxidation, TG secretion, lipogenesis); human hepatocyte primary culture |
Hepatology communications |
Medium |
34278168
|
| 2026 |
PPP4C (protein phosphatase 4 catalytic subunit) interacts with MST4 and reduces its function; MST4 induces phosphorylation and cytoplasmic degradation of YAP1 by influencing the MAP4K2-LATS1/2 cascade, and PPP4C counteracts this to promote YAP1 activation in NSCLC. |
Co-immunoprecipitation; gain/loss-of-function in NSCLC cell lines; phosphorylation and YAP localization assays; in vivo isograft tumor models; NK cell co-culture immune assay |
Cancer letters |
Medium |
41690452
|