Affinage

FCHSD2

F-BAR and double SH3 domains protein 2 · UniProt O94868

Length
740 aa
Mass
84.3 kDa
Annotated
2026-04-28
12 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FCHSD2 is an F-BAR and SH3 domain-containing scaffold protein that couples membrane curvature sensing to ARP2/3-dependent actin polymerization, functioning in clathrin-mediated endocytosis, endosomal recycling, and specialized cytoskeletal maintenance. FCHSD2 forms a ternary complex with CDC42 and N-WASP to stimulate branched actin assembly; ERK1/2-mediated phosphorylation activates FCHSD2 to promote clathrin-coated pit initiation, and its loss redirects EGFR and MET from recycling into lysosomal degradation, altering downstream signaling (PMID:23437151, PMID:30249660, PMID:32678845, PMID:34520816). At endosomes, MICAL-L1 recruits FCHSD2 to generate ARP2/3-dependent branched actin required for endosome fission and receptor recycling upstream of EHD1 (PMID:39382837). In cochlear hair cells, FCHSD2 cooperates with CDC42 to maintain stereocilia integrity—Fchsd2 knockout mice exhibit progressive hearing loss—and its C-terminal PDZ-binding motif directly engages the PDZ3 domain of the deafness-associated protein PDZD7, physically connecting the ankle link complex to the actin cytoskeleton (PMID:35892293, PMID:35695292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 High

    Establishing that FCHSD2 is an actin regulatory scaffold answered the foundational question of what its SH3 domains do: they recruit WASP/N-WASP to activate ARP2/3-dependent actin polymerization, and the protein localizes to stereocilia, implicating it in inner ear biology.

    Evidence In vitro actin polymerization reconstitution with purified proteins plus co-IP and immunofluorescence in cochlear hair cells

    PMID:23437151

    Open questions at the time
    • No in vivo loss-of-function data at this stage
    • Upstream activation signals unknown
    • Cellular function of FCHSD2-dependent actin polymerization unresolved
  2. 2018 High

    Identifying ERK1/2 as the kinase that phosphorylates and activates FCHSD2 resolved how receptor signaling feeds back to the endocytic machinery: activated FCHSD2 drives clathrin-coated pit initiation, making it a direct link between MAPK signaling and clathrin-mediated endocytosis.

    Evidence Kinase inhibitor screen and mass spectrometry substrate identification in NSCLC cells, live-cell CCP imaging, EGFR surface-level quantification upon siRNA knockdown

    PMID:30249660

    Open questions at the time
    • Phosphorylation site(s) and structural consequences not fully defined
    • Whether other kinases contribute is untested
    • Generality beyond EGFR/NSCLC context unclear
  3. 2020 High

    Demonstrating that FCHSD2 loss reroutes EGFR and MET from recycling into Rab7-dependent lysosomal degradation, with compensatory transcriptional upregulation via nuclear ERK, established FCHSD2 as a gatekeeper of receptor fate decisions at the sorting endosome.

    Evidence siRNA knockdown with receptor recycling/degradation assays, subcellular ERK fractionation, epistasis with Rab7 knockdown

    PMID:32678845

    Open questions at the time
    • Direct biochemical mechanism by which FCHSD2 diverts cargo from degradation to recycling not resolved
    • Whether FCHSD2 acts at sorting endosomes or earlier compartments is ambiguous
  4. 2021 Medium

    Showing that FCHSD2 forms a ternary complex with CDC42 and N-WASP and that the F-BAR domain independently drives membrane protrusions clarified how domain architecture couples membrane binding to Rho-GTPase-dependent actin remodeling at the plasma membrane.

    Evidence Co-IP of ternary complex, domain-deletion mutant morphology assays in cultured cells

    PMID:34520816

    Open questions at the time
    • Ternary complex shown in a single lab; independent validation lacking
    • Stoichiometry and direct vs. indirect interactions within the complex not resolved
    • Relevance of protrusions to endocytosis or other physiological contexts unclear
  5. 2021 Medium

    Identifying FCHSD2 as a target of a type 2 diabetes-associated enhancer cluster and showing that its CRISPR knockout impairs glucose-stimulated insulin secretion extended FCHSD2 function to pancreatic β-cell physiology.

    Evidence CRISPR-Cas9 knockout in EndoC-βH1 cells, glucose-stimulated insulin secretion assay, chromatin conformation capture

    PMID:33535042

    Open questions at the time
    • Mechanism linking FCHSD2 to insulin granule exocytosis unknown
    • No in vivo β-cell phenotype reported
    • Whether the endocytic/recycling role explains the insulin secretion defect is untested
  6. 2022 High

    Fchsd2 knockout mice with progressive hearing loss and genetic epistasis with Cdc42 provided the first in vivo demonstration that FCHSD2–CDC42 cooperation is essential for stereocilia structural maintenance, converting earlier localization data into a physiological requirement.

    Evidence Fchsd2 KO and Fchsd2/Cdc42 double KO mice, ABR hearing tests, electron microscopy of stereocilia

    PMID:35892293

    Open questions at the time
    • Whether FCHSD2 acts through N-WASP/ARP2/3 in stereocilia or via a distinct mechanism is unresolved
    • Precise structural defect in actin core of stereocilia not characterized
  7. 2022 High

    A 2.0 Å crystal structure of the FCHSD2 C-terminal tail bound to PDZD7 PDZ3 revealed the atomic basis for coupling the ankle link complex to the cytoskeleton, providing a structural explanation for how FCHSD2 integrates into the hair-cell mechanotransduction apparatus.

    Evidence X-ray crystallography, yeast two-hybrid, co-IP validation in COS-7 cells

    PMID:35695292

    Open questions at the time
    • Functional consequence of disrupting the FCHSD2–PDZD7 interaction in vivo not tested
    • Whether PDZD7 binding modulates FCHSD2 actin-regulatory activity is unknown
  8. 2024 High

    Demonstrating that MICAL-L1 recruits FCHSD2 to endosomes for ARP2/3-dependent branched actin generation upstream of EHD1-mediated fission resolved the molecular order of events in endosomal recycling and identified the mechanism by which FCHSD2 acts in receptor recycling.

    Evidence Reciprocal co-IP, siRNA knockdown with live-cell endosome fission imaging, epistasis between MICAL-L1, FCHSD2, and EHD1

    PMID:39382837

    Open questions at the time
    • How MICAL-L1 recognizes FCHSD2 at the domain level is undefined
    • Whether F-BAR-mediated membrane tubulation by FCHSD2 contributes to fission is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of ERK1/2-mediated FCHSD2 activation, whether FCHSD2's endocytic and recycling roles explain its requirement for insulin secretion, and the extent to which its stereocilia and endosomal functions share a common ARP2/3-dependent mechanism.
  • No structure of full-length FCHSD2 or its F-BAR domain
  • ERK phosphorylation site mapping and conformational activation mechanism incomplete
  • Relationship between endocytic/recycling function and β-cell insulin secretion untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2 R-HSA-9709957 Sensory Perception 2
Partners
CDC42EHD1MICAL-L1PDZD7WASWASL

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 FCHSD2 interacts with WASP and N-WASP and stimulates ARP2/3-dependent F-actin assembly in vitro; FCHSD2 localizes along stereocilia of cochlear hair cells in a punctate pattern Co-immunoprecipitation/pulldown, in vitro actin polymerization assay, immunofluorescence localization PloS one High 23437151
2018 ERK1/2 phosphorylates and activates FCHSD2, and this phosphorylation is required for FCHSD2-dependent clathrin-coated pit (CCP) initiation and clathrin-mediated endocytosis (CME) in NSCLC cancer cells; loss of FCHSD2 increases EGFR cell-surface expression and alters downstream signaling, enhancing cell proliferation and migration Kinase inhibitor screen, identification of ERK1/2 substrate by mass spectrometry/biochemical assay, siRNA knockdown with live-cell imaging of CCPs, EGFR trafficking assays Proceedings of the National Academy of Sciences of the United States of America High 30249660
2020 FCHSD2 loss shunts EGFR and MET trafficking from recycling into late endosomes/lysosomal degradation, causing nuclear translocation of active ERK1/2 and transcriptional upregulation of EGFR and MET; Rab7 is required for these FCHSD2-depletion-induced effects siRNA knockdown, receptor trafficking assays (recycling vs. degradation), subcellular fractionation, epistasis with Rab7 knockdown PLoS biology High 32678845
2021 FCHSD2 promotes apical and lateral cell protrusion formation by cooperating with CDC42 and N-WASP; FCHSD2, CDC42, and N-WASP form a ternary complex; the F-BAR domain of FCHSD2 independently induces lateral protrusions; plasma membrane binding by FCHSD2 is required for protrusion induction Co-immunoprecipitation, overexpression/loss-of-function in cultured cells, domain-deletion mutant analysis, cell morphology assays Biochimica et biophysica acta. Molecular cell research Medium 34520816
2022 FCHSD2 is required for stereocilia maintenance in cochlear hair cells in vivo; Fchsd2 knockout mice show progressive hearing loss and increased acoustic vulnerability; Fchsd2/Cdc42 double knockout shows more severe stereocilia deficits, demonstrating cooperative regulation of stereocilia maintenance Fchsd2 knockout mouse generation, auditory brainstem response (ABR) hearing tests, electron microscopy of stereocilia, double KO epistasis Journal of cell science High 35892293
2022 FCHSD2 C-terminal PDZ-binding motif directly binds the PDZ3 domain of deafness-related protein PDZD7; crystal structure of the complex solved at 2.0 Å reveals the FCHSD2 tail threading through the αB/βB groove of PDZD7 PDZ3, linking the ankle link complex to cytoskeletal dynamics Yeast two-hybrid screening, co-immunoprecipitation in COS-7 cells, X-ray crystallography at 2.0 Å The Biochemical journal High 35695292
2024 MICAL-L1 (endosomal scaffolding protein) directly recruits FCHSD2 to the endosomal membrane, where FCHSD2 is required for ARP2/3-mediated branched actin generation, endosome fission, and receptor recycling to the plasma membrane; MICAL-L1 subsequently recruits EHD1 for nucleotide hydrolysis-based fission, placing FCHSD2 upstream of EHD1 in the endosomal fission pathway Co-immunoprecipitation identifying MICAL-L1–FCHSD2 interaction, siRNA knockdown of FCHSD2, live-cell imaging of endosome fission and recycling, epistasis between MICAL-L1, FCHSD2, and EHD1 Molecular biology of the cell High 39382837
2021 FCHSD2 is an additional transcriptional target of an enhancer cluster at the STARD10/T2D locus; CRISPR-Cas9 loss of FCHSD2 in EndoC-βH1 cells impairs glucose-stimulated insulin secretion CRISPR-Cas9 deletion, glucose-stimulated insulin secretion assay, chromatin conformation capture Cell reports Medium 33535042

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 FCHSD1 and FCHSD2 are expressed in hair cell stereocilia and cuticular plate and regulate actin polymerization in vitro. PloS one 34 23437151
2018 Role for ERK1/2-dependent activation of FCHSD2 in cancer cell-selective regulation of clathrin-mediated endocytosis. Proceedings of the National Academy of Sciences of the United States of America 33 30249660
2004 Identification and characterization of human FCHSD1 and FCHSD2 genes in silico. International journal of molecular medicine 33 15067381
2020 FCHSD2 controls oncogenic ERK1/2 signaling outcome by regulating endocytic trafficking. PLoS biology 15 32678845
2012 FCHSD2 predicts response to chemotherapy in acute myeloid leukemia patients. Leukemia research 9 22902056
2021 Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion. Cell reports 8 33535042
2021 FCHSD2 cooperates with CDC42 and N-WASP to regulate cell protrusion formation. Biochimica et biophysica acta. Molecular cell research 7 34520816
2022 FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells. Journal of cell science 3 35892293
2024 Endosomal actin branching, fission, and receptor recycling require FCHSD2 recruitment by MICAL-L1. Molecular biology of the cell 2 39382837
2022 Deafness-related protein PDZD7 forms complex with the C-terminal tail of FCHSD2. The Biochemical journal 2 35695292
2024 Endosomal actin branching, fission and receptor recycling require FCHSD2 recruitment by MICAL-L1. bioRxiv : the preprint server for biology 0 38979241
2023 IRF3-mediated lncRNA FTX promotes cell proliferation, migration, invasion and suppresses cell apoptosis in oral squamous cell carcinoma by up-regulating FCHSD2 via miR-708-5p. Cellular and molecular biology (Noisy-le-Grand, France) 0 37224049