Affinage

STRIP1

Striatin-interacting protein 1 · UniProt Q5VSL9

Length
837 aa
Mass
95.6 kDa
Annotated
2026-06-10
25 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STRIP1 (FAM40A) is a core structural subunit of the STRIPAK complex, a non-canonical PP2A holoenzyme that links phosphatase activity to germinal center kinase III signaling to control cytoskeletal organization, cell migration, and Hippo-pathway output (PMID:18782753, PMID:25531779). The cryo-EM structure of the human STRIPAK core establishes STRIP1 as a scaffold that incorporates an inositol hexakisphosphate (IP6) cofactor and bridges the STRN3 coiled-coil tetramer to the PP2A A/C dimer, with interface mutations disrupting complex integrity and causing aberrant Hippo activation [#11...,#9]. Functionally, STRIP1 negatively regulates the MST3 and MST4 kinases within STRIPAK; its loss derepresses MST3/4-mediated phosphorylation of PP1-inhibitory PPP1R14 proteins, increasing actomyosin contractility, altering focal adhesions and actin organization, and reshaping cell migration and spreading (PMID:25531779, PMID:29203676). This MST3/4-restraining activity also restrains the cell cycle, as STRIP1 loss induces p21/p27 in a manner rescued by MST3/4 co-depletion (PMID:32258031). STRIP1 constitutes one of two regulatory 'arms' through which STRN3 loads the Hippo kinases (MST1/MST2), and this arm dynamically dissociates in response to decreased cell density, coupling complex assembly to Hippo signaling (PMID:30622739). STRIP1 is essential in vivo for mesoderm migration during mouse development (PMID:29203676), and in other systems it associates with STRN3/striatin to suppress Jun-mediated apoptosis in retinal ganglion cells (PMID:35314028) and to restrain cardiomyocyte hypertrophy via MST1/2/4 (PMID:41892331). STRIP1 orthologs additionally localize to and organize the endoplasmic/sarcoplasmic reticulum and antagonize TORC2 signaling through PP2A (PMID:22298706, PMID:27510976, PMID:37314837).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Established STRIP1 as a bona fide subunit of a defined multiprotein assembly rather than an orphan protein, mapping the compositional architecture of STRIPAK.

    Evidence Iterative reciprocal AP-MS interaction mapping in human cells

    PMID:18782753

    Open questions at the time
    • Did not assign STRIP1 a molecular function within the complex
    • Stoichiometry and architecture unresolved
    • No structural model
  2. 2011 Medium

    Showed STRIP1 and its paralog STRIP2 have non-redundant roles in shaping the actin cytoskeleton and migration, distinguishing the two FAM40 proteins functionally.

    Evidence RNAi knockdown with cell-shape, actin, and migration phenotyping in human cells

    PMID:21834987

    Open questions at the time
    • Mechanism connecting STRIP1 to actin not defined
    • No link to PP2A or kinase activity in this study
    • Single lab
  3. 2012 High

    Connected STRIP1 (via yeast Far11) physically and genetically to PP2A and positioned it as an antagonist of TORC2 signaling.

    Evidence Yeast genetic suppressor screen, co-IP, and TORC2 substrate (Slm1) phosphorylation assay

    PMID:22298706

    Open questions at the time
    • TORC2 antagonism not demonstrated for human STRIP1
    • Direct phosphatase substrate not identified
    • Ortholog-based inference
  4. 2014 High

    Defined the core enzymatic logic: STRIP1 restrains MST3/4 kinases within STRIPAK, controlling actomyosin contractility and context-dependent migration through PPP1R14/PP1.

    Evidence RNAi, reciprocal co-IP, in vitro/in vivo migration and metastasis assays, computational modelling

    PMID:25531779

    Open questions at the time
    • How STRIP1 negatively regulates MST3/4 mechanistically not resolved
    • Direct substrate of the phosphatase not pinpointed
  5. 2016 Medium

    Revealed an ER-associated role, showing the STRIP ortholog organizes ER morphology and is required for receptor membrane localization and stem-cell maintenance.

    Evidence Loss-of-function genetics, immunolocalization, and GLP-1/Notch localization assay in C. elegans

    PMID:27510976

    Open questions at the time
    • Whether human STRIP1 has the same ER role unclear
    • Link between ER function and STRIPAK kinase regulation not established
  6. 2017 High

    Demonstrated an essential in vivo developmental requirement: STRIP1 is needed for mesoderm migration and cytoskeletal/focal-adhesion organization in the mouse embryo.

    Evidence Mouse knockout, embryo phenotyping, mesoderm explant and MEF migration assays with cytoskeletal readouts

    PMID:29203676

    Open questions at the time
    • Whether the phenotype is fully STRIPAK/MST3-4-dependent in vivo not dissected
    • Molecular link to focal adhesion regulation undefined
  7. 2018 Medium

    Extended STRIP1 cytoskeletal control to endothelial and renal cells, placing it upstream of ROCK-mediated contractility and showing a CCM3 interaction.

    Evidence RNAi, co-IP, stress-fiber and angiogenesis assays with ROCK-inhibitor rescue (endothelial); gain/loss-of-function with mutant in podocytes

    PMID:30509168 PMID:30697267

    Open questions at the time
    • Direct biochemical link between STRIP1 and ROCK not shown
    • Nuclear/perinuclear localization in podocytes unreconciled with cytoplasmic complex
    • Single labs
  8. 2019 High

    Showed STRIP1 forms one of two regulatory arms by which STRN3 loads Hippo kinase MST2, with the arm dissociating upon decreased cell density — coupling dynamic complex assembly to Hippo signaling.

    Evidence Co-IP, crystallography of STRN3-SIKE1/SIKE1-SLMAP interfaces, density-dependent dissociation and Hippo reporter assays

    PMID:30622739

    Open questions at the time
    • Signal that triggers density-dependent dissociation unknown
    • Structure of the STRIP1 arm itself not solved here
  9. 2020 Medium

    Placed STRIP1 upstream of MST3/4 in cell-cycle control, showing its loss induces p21/p27 and arrest via MST3/4.

    Evidence RNAi, flow cytometry, single-cell p21/γH2AX immunofluorescence, MST3/4 co-depletion rescue in breast cancer cells

    PMID:32258031

    Open questions at the time
    • How MST3/4 drive p21/p27 induction unresolved
    • Subpopulation specificity (low DDR) mechanism unclear
  10. 2021 High

    Provided the atomic-resolution architecture, establishing STRIPAK as a non-canonical PP2A complex with a STRN3 homotetramer scaffold and STRIP1 bound to an IP6 structural cofactor whose interface integrity gates Hippo output.

    Evidence 3.2-Å cryo-EM of human STRIPAK core (PP2AA/C, STRN3, STRIP1, MOB4) with interface mutagenesis and Hippo activation readout

    PMID:33633399

    Open questions at the time
    • Functional role of the IP6 cofactor not biochemically dissected
    • How density signals are transmitted to this core not shown
  11. 2022 High

    Linked STRIP1 to neuronal survival, showing it acts with STRN3 to suppress pro-apoptotic Jun in retinal ganglion cells.

    Evidence Zebrafish mutants, Strip1-Strn3 co-IP, Jun activation assay, morpholino Jun-knockdown rescue, dendritic patterning analysis

    PMID:35314028

    Open questions at the time
    • Phosphatase/kinase step connecting STRIP1 to Jun not defined
    • Whether MST kinases mediate the apoptotic effect not tested here
  12. 2023 High

    Demonstrated that the STRIP-striatin complex localizes to and organizes the sarcoplasmic reticulum and sarcomere, regulating a Ca²⁺ release channel.

    Evidence Co-IP, SR immunolocalization, missense/deletion mutant analysis, and UNC-68 immunoblot in C. elegans

    PMID:37314837

    Open questions at the time
    • Mechanism by which the complex controls SR/M-line organization unknown
    • Direct effect on UNC-68 vs indirect not resolved
  13. 2024 Medium

    Identified STRIP1 as a negative regulator of cardiomyocyte hypertrophy acting through cardiac STRIPAK and MST1/2/4 kinases, with reduced expression in human cardiomyopathies.

    Evidence siRNA in NRVCMs, nucleolar immunolocalization, STRIPAK co-IP, MST1/2/4 kinase assays, zebrafish morpholino cardiac function assay

    PMID:41892331

    Open questions at the time
    • Nucleolar localization function not mechanistically explained
    • Hippo vs Calcineurin/NFAT contributions not separated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single STRIP1-containing STRIPAK complex selects among its diverse outputs — actomyosin contractility, Hippo signaling, ER/SR organization, cell-cycle arrest, and apoptosis — and how upstream signals such as cell density are transmitted to STRIP1 remains unresolved.
  • No identified direct phosphatase substrate of the STRIP1-PP2A holoenzyme
  • Signal-to-complex transmission mechanism for density-dependent arm dissociation unknown
  • Function of nuclear/nucleolar STRIP1 pools undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1
Complex memberships
STRIPAK

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 STRIP1 (FAM40A) is a novel component of the STRIPAK complex, a large multiprotein assembly containing PP2A catalytic and scaffolding subunits, striatins (PP2A B''' regulatory subunits), Mob3, STRIP2, CCM3, and germinal center kinase III family Ste20 kinases; STRIPAK establishes mutually exclusive interactions with either CTTNBP2 proteins or a subcomplex of SLMAP/SIKE/FGFR1OP2. Iterative affinity purification/mass spectrometry (AP-MS) interaction mapping Molecular & cellular proteomics : MCP High 18782753
2011 FAM40A (STRIP1) depletion by RNAi reduces cell spreading and alters actin filament distribution in human cells, while FAM40B (STRIP2) depletion causes cell elongation and tail retraction defects, indicating that the two paralogs have distinct functions in cytoskeletal organization and cell migration. RNAi knockdown with morphological phenotype scoring (cell shape, actin staining, migration assay) BMC biology Medium 21834987
2012 In yeast, Far11 (ortholog of FAM40A/STRIP1) interacts physically with PP2A components Tpd3 and Pph21, and genetic epistasis shows that deletion of Far11 or PP2A subunits suppresses lethality caused by TORC2 deficiency (lst8Δ, tor2-21), placing Far11 as an antagonist of TORC2 signaling via PP2A. Genetic suppressor screen, co-immunoprecipitation, phosphorylation assay of TORC2 substrate Slm1 Genetics High 22298706
2014 FAM40A (STRIP1) negatively regulates MST3 and MST4 kinases within the STRIPAK complex; loss of FAM40A promotes co-localization of contractile actomyosin machinery with ERM proteins via MST3/4-mediated phosphorylation of PPP1CB inhibitors (PPP1R14A-D), reducing cell speed on planar surfaces but favouring migration in confined environments. FAM40B mutations found in human tumours uncouple it from PP2A, enabling a contractile phenotype. RNAi knockdown, computational modelling, in vitro migration assays, in vivo breast cancer metastasis assays, co-immunoprecipitation Nature cell biology High 25531779
2016 FARL-11, the C. elegans ortholog of STRIP1/2, localizes to the endoplasmic reticulum and is required for cell cycle-dependent ER morphological changes in embryos; in the germline, FARL-11 is required for normal ER morphology and for proper membrane localization of the GLP-1/Notch receptor, which is necessary for germline stem cell maintenance. Loss-of-function genetic analysis, immunofluorescence localization, GLP-1 receptor membrane localization assay in C. elegans Development (Cambridge, England) Medium 27510976
2017 STRIP1 is essential for mesoderm migration in vivo in mouse embryos; Strip1-null mutants arrest at midgestation with failure of anterior axial mesoderm extension, and cultured mesoderm cells from null mutants show decreased spreading, abnormal focal adhesions, disorganized actin cytoskeleton, and reduced migration velocity. Mouse knockout, embryo phenotyping, mesoderm explant culture, mouse embryonic fibroblast migration assays, immunofluorescence for focal adhesions and actin Proceedings of the National Academy of Sciences of the United States of America High 29203676
2018 FAM40A (STRIP1) interacts with CCM3 and its knockdown in endothelial cells increases stress fibers and reduces in vitro angiogenic loop formation; these effects are reverted by ROCK kinase inhibition, placing STRIP1 upstream of ROCK-mediated endothelial contractility. RNAi knockdown, co-immunoprecipitation, stress fiber quantification, in vitro angiogenesis assay, ROCK inhibitor rescue BMC cell biology Medium 30509168
2018 FAM40A (STRIP1) localizes to the nucleus and perinuclear zone in mouse podocytes; its silencing or over-expression alters podocyte morphology and F-actin organization, and a point mutant (p521M>T) causes blunted podocyte morphology, disordered F-actin distribution, and reduced nephrin expression, demonstrating a role in podocyte cytoskeletal integrity. siRNA knockdown, overexpression, mutant overexpression, immunofluorescence, RT-qPCR, Western blot in mouse podocytes Archives of medical science : AMS Medium 30697267
2019 Within the STRIPAK-Hippo complex, STRIP1 constitutes one of two 'arms' by which STRN3 controls loading of the Hippo kinase MST2; a decreased cell density triggers dissociation of the STRIP1 arm from STRIPAK, reflecting dynamic assembly of the complex in response to upstream signals. Disrupting the STRIP1-containing arm abrogates STRIPAK's regulatory effect on Hippo signaling. Co-immunoprecipitation, crystallography (defining STRN3-SIKE1 and SIKE1-SLMAP interfaces), cell-density-dependent dissociation assay, functional Hippo pathway reporter assay Cell discovery High 30622739
2021 Cryo-EM structure of the human STRIPAK core (PP2AA, PP2AC, STRN3, STRIP1, MOB4) at 3.2-Å resolution reveals that STRIPAK is a non-canonical PP2A complex: it contains four copies of STRN3 forming an elongated homotetrameric coiled-coil scaffold. STRIP1 incorporates an inositol hexakisphosphate (IP6) as a structural cofactor. Mutations at subunit interfaces disrupt complex integrity and cause aberrant Hippo pathway activation. Cryo-EM structure determination, interface mutagenesis, Hippo pathway activation assay Nature structural & molecular biology High 33633399
2020 Loss of STRIP1 in MDA-MB-231 breast cancer cells induces cell cycle arrest and decreased proliferation through induction of CDK inhibitors p21 and p27; this induction occurs in a subpopulation with low DNA damage response (p21high/γH2AXlow), and is rescued by co-depletion of MST3 and MST4 kinases, placing STRIP1 upstream of MST3/4 in regulation of p21/p27. RNAi knockdown, flow cytometry, single-cell immunofluorescence for p21/γH2AX, MST3/4 co-depletion rescue Frontiers in cell and developmental biology Medium 32258031
2022 In zebrafish, Strip1 interacts with Striatin 3 (Strn3) and both are required for retinal ganglion cell (RGC) survival; loss of Strip1 or Strn3 activates the pro-apoptotic transcription factor Jun in RGCs, and Jun knockdown rescues RGC survival in strip1 mutants, placing Strip1 upstream of Jun-mediated apoptosis. Strip1 is additionally required for RGC dendritic patterning. Zebrafish genetic mutant analysis, co-immunoprecipitation (Strip1-Strn3 interaction), Jun activation assay, morpholino-mediated Jun knockdown rescue eLife High 35314028
2023 In C. elegans, FARL-11 (STRIP1/2 ortholog) and CASH-1 (striatin) form a complex in vivo and both localize to the sarcoplasmic reticulum (SR); missense mutations or single-amino-acid deletions in farl-11 or cash-1 cause sarcomere disorganization, disruption of SR organization around M-lines, and altered levels of the SR Ca²⁺ release channel UNC-68. Co-immunoprecipitation, immunofluorescence localization, genetic missense/deletion mutant analysis, immunoblot for UNC-68 levels in C. elegans Molecular biology of the cell High 37314837
2024 Strip1 localizes to the nucleolus in neonatal rat ventricular cardiomyocytes (NRVCMs) and acts as a negative regulator of cardiomyocyte hypertrophy; Strip1 knockdown increases cell size and activates the hypertrophic gene program, whereas its expression is reduced in human dilated and ischemic cardiomyopathies. Mechanistically, Strip1 associates with cardiac STRIPAK and modulates MST1/MST2 and MST4 kinase activities, influencing Hippo- and Calcineurin/NFAT-related pro-hypertrophic signaling. Morpholino-driven Strip1 reduction in zebrafish causes impaired cardiac function. siRNA knockdown in NRVCMs, immunofluorescence for nucleolar localization, co-immunoprecipitation for STRIPAK association, kinase activity assay (MST1/2/4), zebrafish morpholino knockdown cardiac function assay Cells Medium 41892331

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Molecular & cellular proteomics : MCP 303 18782753
2013 STRIPAK complexes: structure, biological function, and involvement in human diseases. The international journal of biochemistry & cell biology 185 24333164
2011 Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. BMC biology 166 21834987
2014 STRIPAK components determine mode of cancer cell migration and metastasis. Nature cell biology 148 25531779
2019 Architecture, substructures, and dynamic assembly of STRIPAK complexes in Hippo signaling. Cell discovery 59 30622739
2021 Cryo-EM structure of the Hippo signaling integrator human STRIPAK. Nature structural & molecular biology 48 33633399
2015 The composition and function of the striatin-interacting phosphatases and kinases (STRIPAK) complex in fungi. Fungal genetics and biology : FG & B 48 26439752
2012 TORC2 signaling is antagonized by protein phosphatase 2A and the Far complex in Saccharomyces cerevisiae. Genetics 41 22298706
2019 Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans. PLoS genetics 36 30883543
2017 STRIP1, a core component of STRIPAK complexes, is essential for normal mesoderm migration in the mouse embryo. Proceedings of the National Academy of Sciences of the United States of America 27 29203676
2021 Characterization of Strip1 Expression in Mouse Cochlear Hair Cells. Frontiers in genetics 26 33889175
2017 Fsr1, a striatin homologue, forms an endomembrane-associated complex that regulates virulence in the maize pathogen Fusarium verticillioides. Molecular plant pathology 26 28467007
2022 The STRIPAK component SipC is involved in morphology and cell-fate determination in the nematode-trapping fungus Duddingtonia flagrans. Genetics 23 34849851
2016 A role for post-transcriptional control of endoplasmic reticulum dynamics and function in C. elegans germline stem cell maintenance. Development (Cambridge, England) 15 27510976
2020 The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27. Frontiers in cell and developmental biology 13 32258031
2018 The STRIPAK complex components FAM40A and FAM40B regulate endothelial cell contractility via ROCKs. BMC cell biology 13 30509168
2022 Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation. eLife 10 35314028
2018 FAM40A alters the cytoskeleton of podocytes in familial focal and segmental glomerulosclerosis by regulating F-actin and nephrin. Archives of medical science : AMS 4 30697267
2022 Pan-Cancer Analysis on the Oncogenic Role of Programmed Cell Death 10. Journal of oncology 3 36276268
2025 Association of macrophage colony-stimulating factor 1 and its locus with osteoarthritis: Mendelian randomization and colocalization analysis. Clinical rheumatology 2 41134489
2023 FARL-11 (STRIP1/2) is required for sarcomere and sarcoplasmic reticulum organization in C. elegans. Molecular biology of the cell 2 37314837
2026 Strip1 Is a Novel Negative Regulator of Cardiomyocyte Hypertrophy. Cells 0 41892331
2025 Landscape genomics analysis reveals the genetic basis underlying cashmere goats and dairy goats adaptation to frigid environments. Stress biology 0 40924252
2024 Corrigendum: Characterization of Strip1 expression in mouse cochlear hair cells. Frontiers in genetics 0 39759960
2023 FARL-11 (STRIP1/2) is Required for Sarcomere and Sarcoplasmic Reticulum Organization in C. elegans. bioRxiv : the preprint server for biology 0 36945551

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