STRIP1

STRIP1 is a core structural subunit of the STRIPAK complex — a noncanonical PP2A holoenzyme built on a homotetrameric striatin scaffold — that negatively regulates MST-family kinases to control actomyosin contractility, cell migration, cell survival, and ER/SR organization across metazoan tissues. Cryo-EM and crystallographic studies show STRIP1 forms one of two arms of the STRIPAK assembly, uses inositol hexakisphosphate (IP6) as a structural cofactor, and undergoes cell-density-dependent dissociation that gates Hippo pathway activation (PMID:30622739, PMID:33633399). By restraining MST3/4 kinase activity, STRIP1 prevents aberrant phosphorylation of PPP1R14A-D, thereby controlling the balance between cortical and focal-adhesion-based contractility that dictates cell migration mode and metastatic behavior (PMID:25531779, PMID:29203676). STRIP1 also suppresses Jun-mediated apoptosis in retinal ganglion cells, regulates ER morphology and receptor trafficking, and restrains calcineurin/NFAT pro-hypertrophic signaling in cardiomyocytes (PMID:35314028, PMID:27510976, PMID:41892331).

1. 2008 High

   Identification of STRIP1 as a novel STRIPAK subunit resolved the composition of a previously uncharacterized PP2A-striatin supercomplex and revealed mutually exclusive sub-assemblies within it.

   Evidence Iterative AP-MS with reciprocal bait validations in mammalian cells

   PMID:18782753

   Open questions at the time

   • Functional role of STRIP1 within the complex was unknown
   • Stoichiometry and architecture of the complex were unresolved
   • No disease or organismal phenotype yet linked
2. 2011 Medium

   RNAi screening established that STRIP1 and its paralog STRIP2 have non-redundant roles in cell morphology, with STRIP1 specifically required for normal cell spreading.

   Evidence Genome-wide Drosophila RNAi screen followed by human siRNA knockdown with morphological and actin cytoskeletal phenotyping

   PMID:21834987

   Open questions at the time

   • Molecular target through which STRIP1 controls spreading was not identified
   • Single-lab finding not independently confirmed at the time
3. 2012 Medium

   Genetic epistasis in yeast placed the STRIP1 ortholog Far11 as a negative regulator of TORC2 signaling via PP2A, providing the first pathway-level positioning of STRIP1-family proteins.

   Evidence Suppressor screen, co-immunoprecipitation, and phosphorylation assays in S. cerevisiae

   PMID:22298706

   Open questions at the time

   • Whether mammalian STRIP1 similarly antagonizes mTORC2 was untested
   • Mechanism of PP2A substrate selection was unclear
4. 2014 High

   Mechanistic dissection revealed that STRIP1 restrains MST3/4 kinase activity within STRIPAK, and that its loss hyperactivates a MST3/4→PPP1R14A→actomyosin contractility axis that alters cancer cell migration mode and metastasis in vivo.

   Evidence siRNA, in vitro kinase assays, computational modeling, in vitro migration, and in vivo breast cancer metastasis assays with mutagenesis

   PMID:25531779

   Open questions at the time

   • Structural basis of STRIP1-mediated kinase inhibition was unknown
   • Whether STRIP1 directly contacts MST3/4 or acts through PP2A catalytic activity was unresolved
5. 2016 Medium

   Studies of the C. elegans ortholog FARL-11 demonstrated that STRIP1-family proteins localize to the ER and are required for cell-cycle-dependent ER remodeling and receptor trafficking, extending STRIP1 function beyond the cytoskeleton.

   Evidence Fluorescence localization, RNAi, live ER imaging, and GLP-1/Notch receptor localization in C. elegans embryos and germline

   PMID:27510976

   Open questions at the time

   • Whether mammalian STRIP1 similarly localizes to ER was not shown
   • Mechanism linking STRIPAK to ER membrane dynamics was not defined
6. 2017 High

   Mouse Strip1 knockout proved essential for mesoderm cell migration and embryonic axial extension, confirming a cell-autonomous requirement for STRIP1 in focal adhesion organization and migration in vivo.

   Evidence Mouse knockout, cultured mesoderm explants, MEFs, live imaging, focal adhesion and actin immunofluorescence

   PMID:29203676

   Open questions at the time

   • Specific STRIP1-dependent signaling pathway(s) driving the embryonic phenotype were not fully delineated
   • Tissue-specific conditional knockouts were not reported
7. 2018 Medium

   STRIP1 was shown to interact with CCM3 and regulate endothelial contractility upstream of Rho-ROCK signaling, connecting STRIPAK to cerebral cavernous malformation biology.

   Evidence Co-immunoprecipitation, RNAi, in vitro angiogenesis assay, ROCK inhibitor rescue in endothelial cells

   PMID:30509168

   Open questions at the time

   • Whether STRIP1 loss contributes to CCM pathology in vivo was untested
   • Distinction between STRIP1 and STRIP2 contributions in endothelium was limited
8. 2019 High

   Crystallographic analysis revealed STRIP1 as a structural arm that loads MST2 onto the STRIPAK complex in a phosphorylation-dependent, cell-density-responsive manner, providing the first structural mechanism for Hippo pathway regulation by STRIPAK.

   Evidence Crystallography, biochemical reconstitution, co-immunoprecipitation, cell-density dissociation assays, interface mutagenesis

   PMID:30622739

   Open questions at the time

   • Full atomic-resolution structure of the complete STRIPAK holo-complex was lacking
   • Identity of the upstream signal triggering STRIP1 arm dissociation was unknown
9. 2020 Medium

   Epistasis experiments demonstrated that STRIP1 loss causes cell cycle arrest through MST3/4-dependent upregulation of p21 and p27, establishing a proliferation-control axis downstream of STRIPAK.

   Evidence siRNA knockdown, flow cytometry, single-cell immunofluorescence for p21 and γH2AX, double-knockdown rescue in breast cancer cells

   PMID:32258031

   Open questions at the time

   • Whether cell cycle arrest reflects a direct MST3/4 substrate or an indirect DNA damage response was unresolved
   • Single-lab finding in one cell line
10. 2021 High

    A 3.2-Å cryo-EM structure of the STRIPAK core revealed the noncanonical PP2A architecture with a STRN3 homotetramer scaffold and identified IP6 as a structural cofactor buried within STRIP1, establishing the molecular basis for complex integrity and Hippo regulation.

    Evidence Cryo-EM structure determination, interface mutagenesis, Hippo pathway reporter assays

    PMID:33633399

    Open questions at the time

    • How IP6 incorporation is regulated was not addressed
    • Structure did not include the kinase-loading arms in their MST-bound state
11. 2022 High

    In vivo genetic epistasis in zebrafish showed that Strip1-Strn3 interaction within STRIPAK suppresses Jun-mediated apoptosis in retinal ganglion cells, revealing a pro-survival function in neural circuit formation.

    Evidence Zebrafish loss-of-function genetics, co-immunoprecipitation, Jun morpholino rescue of RGC survival

    PMID:35314028

    Open questions at the time

    • How STRIPAK-mediated kinase regulation connects to Jun transcriptional activation was not defined
    • Whether this pathway operates in mammalian retina was untested
12. 2023 Medium

    C. elegans studies demonstrated that the STRIP1 ortholog FARL-11 and striatin localize to the sarcoplasmic reticulum in muscle and are required for SR organization and normal levels of the Ca²⁺ release channel UNC-68, extending STRIPAK function to SR membrane architecture.

    Evidence Co-immunoprecipitation, immunofluorescence, missense mutant characterization, immunoblot in C. elegans muscle

    PMID:37314837

    Open questions at the time

    • Whether mammalian STRIP1 plays a similar role in cardiac SR was not established
    • Mechanism by which STRIPAK regulates UNC-68/RyR levels was not identified
13. 2026 Medium

    Strip1 was found to localize to the nucleolus in cardiomyocytes and to suppress hypertrophy by restraining MST1/2, MST4, and Calcineurin/NFAT signaling, with Strip1 reduction causing impaired cardiac function in zebrafish.

    Evidence siRNA in neonatal rat ventricular cardiomyocytes, immunofluorescence, zebrafish morpholino, kinase and NFAT reporter assays

    PMID:41892331

    Open questions at the time

    • Nucleolar localization of STRIP1 in cardiomyocytes has not been independently confirmed
    • Mechanism linking STRIPAK to calcineurin/NFAT is not molecularly defined
    • In vivo cardiac-specific knockout data in mammals are lacking

• Key unresolved questions include the upstream signal(s) that trigger cell-density-dependent STRIP1 dissociation from STRIPAK, the direct substrates of STRIP1-regulated PP2A activity, the structural basis of the complete kinase-loaded STRIPAK holo-complex, and whether STRIP1 loss is causative for any human Mendelian disease.
• No direct PP2A substrates mediated by STRIP1 have been identified
• Full holo-complex structure with kinase arms unresolved
• No human disease causally linked to STRIP1 mutations