STRN3

STRN3 (SG2NA) is a striatin-family scaffold and regulatory subunit of protein phosphatase 2A (PP2A) that couples the phosphatase to specific substrates and signaling outputs (PMID:11160832, PMID:32589942). It binds the PP2A A/C heterodimer in a manner independent of catalytic-subunit methylation at Leu309, with unmethylated C subunit favoring the interaction (PMID:11160832). Through its C-terminal WD-40 domain, STRN3 recruits MST1/2 kinases to PP2A and promotes their dephosphorylation, thereby inactivating Hippo signaling and activating YAP; a structure-guided peptide that disrupts the STRN3–PP2A interface reactivates Hippo signaling and suppresses tumor growth in vivo (PMID:32589942). STRN3 also assembles a trimeric complex with the antioxidant protein DJ-1 and the kinase Akt at mitochondria and the plasma membrane—the WD-40 domain engaging Akt and a region upstream binding DJ-1—where it protects DJ-1 from proteasomal degradation and shields cells from oxidative stress-induced apoptosis (PMID:25035075, PMID:26022125). Its own abundance is controlled by GSK3β-mediated phosphorylation that stabilizes the protein, counteracted by ERK, and STRN3 levels in turn influence cell-cycle progression and the ER stress response (PMID:28790387, PMID:28634818). Alternative splicing generates isoforms that differ in structure, stability, and binding affinity for DJ-1 and calmodulin, and STRN3 binds calmodulin in a Ca2+-dependent manner (PMID:10748158, PMID:30132185). A recurrent STRN3–PDGFRB fusion that retains the STRN3 coiled-coil domain produces a transforming chimeric kinase causing MDS/MPN-like disease in mice (PMID:37550570).

1. 2000 Medium

   Established STRN3/SG2NA as a Ca2+-responsive scaffold by demonstrating Ca2+-dependent calmodulin binding and dual cytosolic/membrane localization in neurons.

   Evidence Calmodulin-binding assay, subcellular fractionation, and immunostaining with domain-specific antibodies

   PMID:10748158

   Open questions at the time

   • Functional consequence of calmodulin binding not defined
   • No link to phosphatase activity established at this stage
2. 2001 High

   Defined how STRN3 docks onto PP2A, showing binding to the A/C heterodimer does not require C-subunit methylation—distinguishing it from methylation-dependent B subunits and clarifying the assembly logic of striatin-containing PP2A.

   Evidence PP2A C-subunit mutant panel with methylation-selective antibodies and recombinant methylesterase demethylation assay

   PMID:11160832

   Open questions at the time

   • Substrates of the STRN3-PP2A complex not yet identified
   • Structural basis of methylation-independent binding not resolved
3. 2001 Medium

   Mapped intramolecular functional architecture, showing the N-terminus can activate transcription while the WD-40 repeats are repressive and interchangeable with other WD-40 modules.

   Evidence Yeast and mammalian reporter assays with WD-40 domain swaps and GAL4-VP16 chimeras

   PMID:11570823

   Open questions at the time

   • Physiological relevance of transcriptional activity unclear
   • No endogenous target genes identified
4. 2008 Low

   Catalogued STRN3 isoforms (alpha/beta) and their tissue/developmental expression, framing them as PP2A regulatory subunits.

   Evidence Molecular cloning, RT-PCR, and western blot across tissues and developmental stages

   PMID:19838339

   Open questions at the time

   • PP2A subunit role inferred by homology rather than demonstrated biochemically here
   • Functional differences between isoforms not tested
5. 2014 Medium

   Revealed a cytoprotective scaffolding role by identifying a STRN3–DJ-1–Akt trimeric complex at mitochondria/membrane that defends against oxidative stress.

   Evidence Reciprocal co-IP, domain-deletion mapping, co-localization imaging, and knockdown/overexpression apoptosis assays

   PMID:25035075

   Open questions at the time

   • Whether PP2A activity is involved in this complex untested
   • Mechanism linking complex to apoptosis resistance not detailed
6. 2015 Medium

   Extended the cytoprotective role, showing STRN3 stabilizes DJ-1 against proteasomal degradation and supports cancer cell growth, with ROS enhancing complex assembly.

   Evidence shRNA knockdown, proteasome inhibition, co-IP/co-localization, and proliferation/colony-formation assays

   PMID:26022125

   Open questions at the time

   • Direct E3 ligase or degradation pathway for DJ-1 not identified
   • In vivo relevance to tumor growth not tested here
7. 2017 Medium

   Defined regulation of STRN3 stability and its reciprocal influence on signaling, showing GSK3β phosphorylation stabilizes it, ERK opposes this via GSK3β, and STRN3 levels feed back on pERK/pGSK3β and cell-cycle phase.

   Evidence Pharmacological kinase/phosphatase inhibition, shRNA knockdown, proteasome inhibition, and cell-cycle analysis

   PMID:28790387

   Open questions at the time

   • Direct phosphosites on STRN3 not mapped
   • Mechanism of feedback on ERK/GSK3β unresolved
8. 2017 Medium

   Connected STRN3 to ER stress and cell-cycle control, showing depletion triggers ER stress and G1 arrest while ER stressors upregulate and relocalize STRN3.

   Evidence shRNA knockdown with proteome analysis, ER stressor treatment, fractionation, cell-cycle analysis, and in vivo mouse injection

   PMID:28634818

   Open questions at the time

   • Molecular link between STRN3 loss and ER stress induction unknown
   • Isoform-specific contribution not dissected beyond 78 kDa form
9. 2018 Medium

   Demonstrated that alternative splicing yields biophysically and functionally distinct STRN3 isoforms differing in stability and partner affinity.

   Evidence Circular dichroism, thermal denaturation, and in vitro binding assays with purified 87 and 78 kDa isoforms

   PMID:30132185

   Open questions at the time

   • In vivo functional divergence of isoforms not established
   • Structural basis for affinity differences unresolved
10. 2020 High

    Established the core oncogenic mechanism: STRN3-PP2A recruits and dephosphorylates MST1/2 to inactivate Hippo and activate YAP, and showed this interface is druggable.

    Evidence Co-IP, in vitro phosphatase assay, structure-guided peptide inhibitor (SHAP), and in vivo tumor xenografts with gain/loss of function

    PMID:32589942

    Open questions at the time

    • How STRN3 selects MST1/2 over other substrates not fully defined
    • Relationship between Hippo regulation and the DJ-1/Akt scaffold role unexplored
11. 2023 Medium

    Implicated STRN3 in leukemogenesis via a STRN3-PDGFRB fusion whose coiled-coil drives constitutive kinase activation.

    Evidence RT-PCR/sequencing of fusion transcript, Ba/F3 transformation assay, mouse transplantation model, and imaging

    PMID:37550570

    Open questions at the time

    • Contribution of STRN3 domains beyond oligomerization not dissected
    • Whether endogenous STRN3 functions are perturbed by the fusion unknown

• How STRN3's distinct roles—Hippo/YAP regulation via PP2A, DJ-1/Akt cytoprotection, and cell-cycle/ER-stress control—are integrated, and how isoform identity and localization partition these functions, remains unresolved.
• No unified structural or spatial model linking the substrate-recruitment functions
• Isoform-specific in vivo roles not defined
• Physiological substrate repertoire of STRN3-PP2A incompletely mapped