STRN4

STRN4 is a scaffold protein and core component of the STRIPAK complex that targets PP2A phosphatase activity toward Hippo pathway kinases to control YAP/TAZ activity and cell behavior (PMID:36757811, PMID:25250919). As a STRIPAK subunit, STRN4 directly associates with MAP4K-family kinases including MINK1, TNIK, and MAP4K4, and its depletion suppresses cancer cell proliferation, migration, invasion, anchorage-independent growth, and in vivo metastasis (PMID:32640226, PMID:25250919). Mechanistically, STRN4 mediates PP2A binding to and dephosphorylation of the Hippo kinases MST1/2, stabilizing YAP/TAZ; loss of STRN4/PP2A raises MST1/2 activity, and in tumor-associated macrophages this antagonizes STING-driven type I interferon responses (PMID:36757811). Palmitoylation of STRN4 at Cys701 by DHHC9 reduces YAP phosphorylation, promotes nuclear YAP translocation, and induces the transcriptional targets CCN1, CCN2, and ANKRD1 to drive cancer cell migration (PMID:40903842). STRN4 expression is induced by the transcription factor Pokemon (LRF), which binds the STRN4 promoter to promote proliferation and suppress apoptosis (PMID:31205540). Beyond cancer, STRN4 localizes to mushroom-type dendritic spines where it maintains spine morphology through PP2A in an NMDA receptor-dependent manner (PMID:28442576).

1. 2014 Medium

   Established STRN4 as a physical hub linking GCK-family kinases to a large protein complex with a causal role in malignancy, framing it as more than a passive scaffold.

   Evidence Co-IP of STRN4 with MINK1/TNIK/MAP4K4 plus siRNA/shRNA loss-of-function in proliferation, invasion, and xenograft metastasis assays

   PMID:25250919

   Open questions at the time

   • Did not define which phosphatase activity STRN4 directs
   • Direct vs. indirect kinase association within the complex not resolved
   • Mechanism connecting kinase binding to the cancer phenotype unspecified
2. 2017 Medium

   Showed STRN4 has a tissue-specific structural role in neurons, demonstrating PP2A-dependent function distinct from its cancer context.

   Evidence Spine morphology analysis with STRN4 knockdown, PP2A interaction assays, NMDA receptor blockade, and dendritic mRNA localization in neurons

   PMID:28442576

   Open questions at the time

   • PP2A substrate in spines not identified
   • Link between NMDA-driven local translation and spine maintenance mechanistic detail unclear
   • Relationship to Hippo signaling in neurons untested
3. 2019 Medium

   Identified an upstream transcriptional driver of STRN4, explaining how its expression is elevated in cancer.

   Evidence ChIP showing Pokemon/LRF binding to the STRN4 promoter with knockdown and proliferation/apoptosis readouts in prostate cancer cells

   PMID:31205540

   Open questions at the time

   • Single study, single cancer type
   • Whether Pokemon regulation operates in other tissues unknown
   • Downstream STRN4 effectors in this axis not dissected
4. 2020 Medium

   Defined STRN4 as a generic STRIPAK-borne binding partner of the entire MAP4K family, generalizing the 2014 finding into a pathway-level scaffold role in Hippo signaling.

   Evidence AP-MS interactome mapping of MAP4K-family kinases in endometrial cancer

   PMID:32640226

   Open questions at the time

   • Interactome alone does not establish directionality of regulation
   • Functional consequence of each MAP4K interaction not separated
   • Phosphatase targeting mechanism not demonstrated here
5. 2023 High

   Resolved the core enzymatic mechanism: STRN4 couples PP2A to MST1/2 dephosphorylation to stabilize YAP/TAZ, and connected this to innate immune signaling output.

   Evidence Reciprocal Co-IP, MST1/2 dephosphorylation assays, PP2A/STRN4 knockdown/knockout, and macrophage-specific PP2A-deficient mouse tumor models

   PMID:36757811

   Open questions at the time

   • Stoichiometry of the STRN4-PP2A-MST complex not defined
   • Whether STRN4 distinguishes MST1 vs MST2 unclear
   • Generality of the YAP-STING antagonism beyond macrophages untested
6. 2025 High

   Added a post-translational switch—DHHC9 palmitoylation at Cys701—that tunes STRN4 activity toward nuclear YAP and a pro-migratory transcriptional program.

   Evidence Palmitoylation site mapping, C701 mutagenesis, YAP phosphorylation and nuclear fractionation assays, DHHC9 knockdown, and in vitro/in vivo metastasis assays

   PMID:40903842

   Open questions at the time

   • How palmitoylation alters STRN4-PP2A or STRN4-membrane behavior mechanistically unresolved
   • Reversibility/depalmitoylation regulation not characterized
   • Whether palmitoylation regulates the neuronal pool of STRN4 unknown

• How STRN4's distinct activities—cancer Hippo regulation, immune modulation, and neuronal spine maintenance—are coordinated and whether they share common substrate logic remains unresolved.
• No structural model of the STRN4-PP2A-MST/MAP4K assembly
• Full PP2A substrate repertoire directed by STRN4 unknown
• Crosstalk between palmitoylation, transcriptional induction, and tissue context not integrated