Affinage

FHOD1

FH1/FH2 domain-containing protein 1 · UniProt Q9Y613

Length
1164 aa
Mass
126.6 kDa
Annotated
2026-06-09
50 papers in source corpus 30 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHOD1 is a diaphanous-related formin that nucleates and organizes actin filaments to drive stress fiber maturation, cell spreading, migration, force generation, and nuclear positioning (PMID:12665555, PMID:24331927, PMID:31657439). In its resting state the protein is held in a closed, autoinhibited conformation through an intramolecular interaction between the N-terminal FH3/DID region and a C-terminal DAD; the DAD is intrinsically unstructured with a hydrophobic autoregulatory motif and a basic cluster, and an extended polybasic region unique to the FHOD subfamily stabilizes this autoinhibited complex (PMID:14576350, PMID:16361249, PMID:41448430). Activation is principally driven by ROCK, which phosphorylates Ser1131, Ser1137, and Thr1141 to disrupt the autoinhibitory interaction downstream of Rho/GPCR signaling such as thrombin stimulation (PMID:18239683); FHOD1 binds ROCK1 directly through its FH2 domain and is targeted to integrin clusters by Src family kinases upstream of ROCK during adhesion formation (PMID:18694941, PMID:24331927). Once relieved of autoinhibition, the FH1 and FH2 domains drive formation of thick actin stress fibers, biasing precursor populations toward transverse arc and ventral stress fiber maturation while restraining dorsal fiber elongation, and coordinating actomyosin bundle maturation with centripetal flow (PMID:12857739, PMID:24481812, PMID:31657439). At the nucleus, FHOD1 binds nesprin-2 giant (and nesprin-1G) spectrin repeats to provide a second attachment point that couples the nucleus to moving dorsal actin cables, forming TAN lines required for nuclear movement and centrosome orientation; structural work redefined the presumed GTPase-binding domain as a spectrin-repeat-binding enhancer for the adjacent FH3 domain (PMID:24880667, PMID:33472039). FHOD1 activity is further tuned by additional post-translational modifications: PKGIα phosphorylates Ser1131 in response to cGMP to weaken its own interaction with FHOD1, Aurora-B phosphorylation coordinates post-mitotic actin cable assembly, and PRMT7 methylation of DAD arginines is mutually antagonistic with ROCK phosphorylation (PMID:15051728, PMID:23613471, PMID:39368550). Beyond the cytoskeleton, FHOD1 also feeds into MRTF-A/SRF-dependent transcription (PMID:22144583).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 Medium

    Established that FHOD1 binds a specific GTPase and is held inactive by intramolecular autoregulation, framing it as a switchable cytoskeletal effector rather than a constitutive one.

    Evidence Yeast two-hybrid, co-IP, and SRE reporter assays mapping Rac1 binding and N-/C-terminal autoinhibitory regions

    PMID:11590143

    Open questions at the time
    • GTPase specificity (Rac vs Rho) for downstream cytoskeletal effects unresolved
    • molecular basis of the intramolecular contact not defined
    • no actin-nucleation activity demonstrated
  2. 2003 Medium

    Showed that relieved FHOD1 nucleates actin stress fibers via FH1/FH2 and operates downstream of the Rho-ROCK cascade, placing it in a defined signaling-to-cytoskeleton pathway and linking it to cell migration.

    Evidence Constitutively active/truncation mutants, dominant-negative GTPases, C3/Y-27632 inhibitors, F-actin binding, and migration assays in NIH3T3 cells

    PMID:12665555 PMID:12857739 PMID:14576350

    Open questions at the time
    • how Rac binding relates to Rho-ROCK activation mechanistically unclear
    • no direct biochemical actin assembly kinetics
    • physiological activating stimulus not identified
  3. 2004 Medium

    Identified FHOD1 as a direct PKGI substrate and a partner of additional receptors and adaptors, broadening the input signals and protein context that regulate it.

    Evidence Y2H, GST pull-down, in vitro kinase assay defining Ser1131, plus co-IP/co-localization with CD21 and FH1-domain partners (WISH-B, cyclophilin B, PRKCBP1)

    PMID:15051728 PMID:15095401 PMID:15138285

    Open questions at the time
    • functional consequence of Ser1131 phosphorylation on actin activity at the time unresolved
    • physiological relevance of CD21 binding limited to EBV context
    • FH1-partner functions only partially characterized
  4. 2005 Medium

    Defined the structural and oligomeric basis of FHOD1 autoinhibition and activation, and linked Src and ERK signaling to distinct FHOD1 outputs (transcription vs stress fibers).

    Evidence NMR of the DAD, in vitro DAD-FH3 binding/mutagenesis, coiled-coil deletion, Src/MEK inhibition with reporter assays, microtubule co-organization assays

    PMID:15642356 PMID:15878344 PMID:16112087 PMID:16169515 PMID:16361249

    Open questions at the time
    • DAD-FH3 release trigger in cells not yet mapped to a kinase
    • ERK pathway link is a single-lab co-IP without reciprocal validation
    • separation of transcriptional vs cytoskeletal mechanisms incomplete
  5. 2006 Medium

    Revealed a caspase-3-dependent processing of FHOD1 generating a nuclear/nucleolar C-terminal fragment that represses RNA polymerase I, extending FHOD1 function into apoptotic nuclear regulation.

    Evidence Caspase cleavage assay with site mutagenesis, confocal localization, and BrUTP run-on transcription assay

    PMID:17013756

    Open questions at the time
    • physiological role of the nuclear fragment in apoptosis unclear
    • mechanism of Pol I repression not defined
    • relationship to cytoskeletal function unknown
  6. 2008 High

    Identified ROCK as the principal activating kinase, mapping three phosphosites that disrupt autoinhibition, and provided the N-terminal crystal structure redefining the GBD and FH3 architecture.

    Evidence In vitro kinase assay with site-directed mutagenesis (Ser1131/Ser1137/Thr1141), thrombin stimulation, RNAi, reciprocal ROCK1 domain-mapping co-IP, and X-ray crystallography of GBD/FH3

    PMID:18239683 PMID:18694941 PMID:18786395

    Open questions at the time
    • how Src targeting and ROCK activation are coordinated spatially not fully resolved
    • structure of the full autoinhibited complex absent
    • in vivo significance of bleb formation unclear
  7. 2011 Medium

    Placed FHOD1 within the MRTF-A/SRF transcriptional circuit, showing it feeds back on contractile gene expression and is itself regulated by miR-200c.

    Evidence miR-200c modulation, siRNA, MRTF-A localization, SRF reporter, and MLC2 immunoblotting

    PMID:22144583

    Open questions at the time
    • direct vs actin-dynamics-mediated effect on MRTF-A not separated
    • single-lab pathway placement
    • in vivo relevance not established
  8. 2013 High

    Established FHOD1 as a Src-recruited early effector at integrin adhesions controlling force generation, and extended its roles to pathogen actin tails and post-mitotic actin assembly via Aurora-B.

    Evidence Force-sensing pillar arrays with siRNA and Src co-IP, vaccinia actin-tail epistasis/rescue with Rac1, and Aurora-B phosphomutant assays with APC/C(Cdh1) manipulation

    PMID:23613471 PMID:24062339 PMID:24331927

    Open questions at the time
    • Aurora-B phosphosite functional integration with ROCK sites unresolved
    • molecular link between Src targeting and ROCK activation incompletely defined
    • Rac1-dependent recruitment mechanism not biochemically detailed
  9. 2014 High

    Defined FHOD1's direct role in nuclear positioning through nesprin-2G binding and clarified its differential control of stress fiber subtypes, while localizing it to cardiomyocyte junctions.

    Evidence Co-IP and live imaging of TAN lines/nuclear movement, domain-mutant stress fiber analyses, and intercalated disc fractionation/localization in cardiomyocytes

    PMID:24481812 PMID:24880667 PMID:25125170

    Open questions at the time
    • how FHOD1 simultaneously bundles actin and binds nesprin not structurally resolved here
    • regulation of FHOD1 at the nuclear envelope unclear
    • functional role at intercalated discs not tested
  10. 2017 Medium

    Positioned FHOD1 as the ROCK-dependent effector downstream of the LINC complex in mechanosensing, linking laminopathy mutations to excess contractility through FHOD1.

    Evidence Traction force microscopy with patient-derived LMNA/SYNE-1 mutant cells, siRNA rescue, and ROCK inhibition

    PMID:28455503

    Open questions at the time
    • direct molecular link between LINC complex and ROCK activation not defined
    • single-lab study
    • tissue-level disease relevance not established
  11. 2021 High

    Structurally redefined the FHOD1 'GBD' as a spectrin-repeat-binding enhancer for FH3, explaining nesprin engagement and the overlapping roles of nesprin-1G and nesprin-2G in actin-cable recruitment.

    Evidence X-ray crystallography of FHOD1-nesprin spectrin-repeat complexes with binding assays

    PMID:33472039

    Open questions at the time
    • whether spectrin-repeat binding and actin bundling are simultaneous unresolved
    • regulation of nesprin binding in cells not addressed
    • relation to GTPase binding reported earlier requires reconciliation
  12. 2024 Medium

    Demonstrated a PTM crosstalk code at the DAD: PRMT7 methylation of arginines is mutually exclusive with ROCK phosphorylation of the adjacent serine, adding a regulatory layer to FHOD1 activation.

    Evidence In vitro PRMT7 methylation and ROCK1 kinase assays with site-directed mutagenesis

    PMID:39368550

    Open questions at the time
    • primarily characterized for FHOD3 with extension to FHOD1
    • cellular consequence of methylation not shown
    • no demonstration of dynamic switching in vivo
  13. 2025 Medium

    Refined the structural model of FHOD1 autoinhibition, identifying a subfamily-unique polybasic region that stabilizes the DID-DAD complex and is disrupted upon phosphorylation-dependent activation.

    Evidence AlphaFold3 modeling validated by site-directed mutagenesis and cell-based actin remodeling assays

    PMID:41448430

    Open questions at the time
    • no experimental structure of the autoinhibited complex
    • single-lab computational model
    • quantitative contribution of polybasic region to activation kinetics unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple inputs (Src targeting, ROCK/PKGI/Aurora-B phosphorylation, PRMT7 methylation, GTPase binding) are integrated to set FHOD1 activity in space and time, and the in vivo significance of its proposed roles in ferroptosis and hypertensive remodeling, remain unresolved.
  • no unified structural model of the full-length autoinhibited-to-active transition
  • ferroptosis (HSPB1) and RNF213/hypertension links rest on low-confidence rescue assays without direct biochemistry
  • no integrated quantitative model of competing PTMs

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005635 nuclear envelope 2 GO:0005886 plasma membrane 2 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-9609507 Protein localization 1
Partners
AURKBPRKG1PRMT7RAC1ROCK1SRCSYNE1SYNE2
Complex memberships
LINC complex (nesprin/SUN)TAN lines

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 FHOD1 (FHOS) interacts with the polybasic domain of Rac1 C-terminus in a guanine nucleotide-independent manner but does not bind RhoA, Cdc42Hs, Rac2, or Rac3. Intramolecular autoinhibitory interactions between the C-terminus of FHOS and an N-terminal region partially overlapping the Rac1 interaction domain were identified. Truncation mutants lacking either the N- or C-terminal autoregulatory domains stimulated transcription from the SRE reporter, indicating these regions suppress activity. Yeast two-hybrid, co-immunoprecipitation, reporter gene assay, immunofluorescence The Journal of biological chemistry Medium 11590143
2003 A constitutively active form of FHOD1 associates with F-actin and induces thick actin stress fibers in NIH3T3 cells via FH1 and FH2 domains. These cytoskeletal effects require the Rho-ROCK cascade (acting downstream of Rho) but Rac1 (not Rho or Cdc42) binds FHOD1 in cells and recruits it to actin filaments and lamellipodia/membrane ruffles. Activated FHOD1 also interferes with lamellipodia formation. Co-immunoprecipitation, dominant-negative GTPase expression, pharmacological inhibitors (C3, Y-27632), immunofluorescence, SRE-reporter assay The Journal of biological chemistry Medium 12857739
2003 Fhos (FHOD1) in its active form induces actin stress fibers. The protein normally exists in a closed inactive form via intramolecular interaction between the N-terminal region and the C-terminal DAD. Both FH1 and FH2 domains are required for stress fiber induction, but the N-terminal region mediates F-actin binding required for targeting to stress fibers. Fhos forms a homotypic complex via direct FH2 domain self-association in cells. In vitro F-actin binding assay, co-immunoprecipitation, deletion mutant analysis, immunofluorescence Journal of cell science Medium 14576350
2003 Full-length FHOD1 co-localizes with filamentous actin at cell peripheries and enhances cell migration to collagen and fibronectin. The FH1 and FH2 domains are required for stress fiber formation. A C-terminal truncation (ΔC, 1-1010) lacking the autoinhibitory domain induces prominent stress fibers sensitive to dominant-negative Rac, C3 transferase, and Y-27632, placing FHOD1 downstream of Rac and Rho-ROCK. Stable overexpression, migration assays (Boyden chamber/transwell), immunofluorescence, pharmacological inhibition Journal of cell science Medium 12665555
2004 FHOD1 is a direct binding partner and phosphorylation substrate of cyclic GMP-dependent protein kinase I (PKGI) in vascular smooth muscle cells. The FHOD1 C-terminus (aa 964-1165) binds full-length PKGIα, and this interaction is decreased 3- to 5-fold by the PKG activator 8Br-cGMP. PKGI directly phosphorylates FHOD1 at Ser-1131 in vitro and in intact cells. Yeast two-hybrid, GST pull-down, in vitro kinase assay, intact cell phosphorylation assay, site-directed mutagenesis of peptides The Journal of biological chemistry High 15051728
2004 FHOD1 binds the cytoplasmic domain of the EBV receptor CD21 through its C-terminus. EBV binding to CD21 stimulates plasma membrane aggregation, redistribution, and co-localization of FHOD1 with CD21. FHOD1 (FHOS) localizes to the cytoplasm and accumulates with actin in membrane protrusions when expressed in cells. Co-immunoprecipitation, co-localization by confocal microscopy, EBV stimulation assay Journal of cell science Medium 15138285
2004 FHOD1 interacts with WISH-B (isoform of WASP-interacting SH3-domain protein/diaphanous-interacting protein), cyclophilin B, and PRKCBP1 via its FH1 domain. WISH-B altered the solubility of FHOD1 in vitro, and a WISH-B truncation mutant (aa 1-227) disrupted FHOD1-induced stress fibers without affecting FHOD1-mediated SRF-dependent gene transcription. Stabilization of F-actin prevented FHOD1-dependent SRF promoter activation in high serum. Yeast two-hybrid screen, in vitro binding/solubility assay, immunofluorescence, reporter gene assay Journal of cellular biochemistry Medium 15095401
2005 Active FHOD1 coordinates actin stress fibers with microtubules, causing parallel alignment of microtubules and cell elongation. FH1 and FH2 domains are both strictly required for these cytoskeletal effects. Formation of FHOD1-actin fibers is a prerequisite for microtubule polarization, but sustained cell elongation requires both filament systems simultaneously. These effects depend on Rho-ROCK cascade activity but not Rac or Cdc42. Expression of constitutively active FHOD1 deletion mutants, pharmacological depolymerization of actin (cytochalasin D) or microtubules (nocodazole), dominant-negative GTPase expression, immunofluorescence Experimental cell research Medium 15878344
2005 FHOD1 contains a C-terminal 60-amino acid DAD that recognizes an N-terminal FH3 domain to establish autoinhibition. The FH3 domain of FHOD1 does not overlap with the Rac1-binding domain. The DAD contains one functional hydrophobic autoregulatory motif and a basic cluster; simultaneous mutation of both efficiently releases autoinhibition, inducing stress fibers and SRE transcription. NMR analysis shows the FHOD1 DAD is intrinsically unstructured with a tendency for helical conformation at the hydrophobic motif. In vitro binding assay, site-directed mutagenesis, NMR spectroscopy, size exclusion chromatography, cell-based reporter assay and immunofluorescence The Journal of biological chemistry High 16361249
2005 FHOD1 oligomerizes via a coiled-coil motif C-terminal to the core FH2 domain. Deletion of this coiled-coil motif abrogates FHOD1-induced actin stress fibers and SRE transcriptional activation, but does not disrupt physical or functional interaction with Rac1, indicating oligomerization is separately required for cytoskeletal and transcriptional activities. Yeast two-hybrid, co-immunoprecipitation, co-localization, deletion mutant cell-based assays FEBS letters Medium 15642356
2005 Src kinase activity is required for FHOD1 distribution to lamellipodia and for FHOD1-induced SRE and skeletal actin promoter gene expression, but Src inhibition does not affect constitutively active FHOD1-induced stress fiber formation. Additionally, Src activity is necessary to maintain FHOD1 mRNA levels. Pharmacological Src inhibition, dominant-negative constructs, reporter gene assay, immunofluorescence Biochemical and biophysical research communications Medium 16169515
2005 FHOD1 co-precipitates with components of the ERK MAP kinase pathway (but not p38 or JNK) and co-localizes with Raf-1 at lamellipodia and MEK at stress fibers. FHOD1-induced SRE gene expression is dependent on ERK MAP kinase activation, whereas FHOD1-induced stress fiber formation and skeletal actin promoter transcription are ERK-independent. Co-immunoprecipitation, immunofluorescence co-localization, pharmacological MEK inhibition, reporter gene assay Biochemical and biophysical research communications Low 16112087
2006 Caspase-3 cleaves FHOD1 at the SVPD(616) site during apoptosis. The N-terminal cleavage product is distributed diffusely in cytoplasm and nucleoplasm, while the C-terminal cleavage product localizes almost exclusively to the nucleus with nucleolar enrichment and inhibits RNA polymerase I transcription (blocks BrUTP incorporation in run-on transcription assay). Caspase cleavage assay, site identification by mutagenesis, confocal microscopy, run-on transcription assay with BrUTP Apoptosis Medium 17013756
2008 ROCK phosphorylates FHOD1 at C-terminal residues Ser1131, Ser1137, and Thr1141, fully disrupting autoinhibitory intramolecular interaction between the N- and C-terminal regions, culminating in stress fiber formation. In vascular endothelial cells, thrombin (via G protein-coupled receptor→Rho→ROCK) elicits FHOD1 phosphorylation and stress fiber formation in a ROCK-dependent manner; FHOD1 depletion by RNAi impairs thrombin-induced stress fiber formation. In vitro kinase assay, site-directed mutagenesis, intramolecular interaction assay, RNAi knockdown, thrombin stimulation, immunoblot with phospho-specific antibodies The EMBO journal High 18239683
2008 FHOD1 physically associates with ROCK1 via the N-terminal part of its FH2 domain binding the central domain of ROCK1. FHOD1 is an efficient ROCK1 phosphorylation substrate. Co-expression of FHOD1 and ROCK1 generates nonapoptotic plasma membrane blebs to which FHOD1 is recruited. Blebbing depends on F-actin integrity, the Rho-ROCK cascade, and Src activity. Efficient association of FHOD1 with ROCK1 and recruitment to blebs requires Src activity. Co-immunoprecipitation, domain mapping, in vitro kinase assay, RNAi knockdown, cell morphology assays in 2D and 3D matrices The Journal of biological chemistry High 18694941
2008 Crystal structure of the N-terminal domains of FHOD1 (GBD and FH3) was determined. The FHOD1 GBD has a ubiquitin superfold (distinct from mDia1's GBD), and is recruited by Rac and Ras GTPases in cells and required for FHOD1-mediated actin remodeling. The FH3 domain is composed of five armadillo repeats. Mutation of one residue in the predicted DAD-interaction surface of FH3 efficiently activates FHOD1 in cells. X-ray crystallography, GTPase binding assays, site-directed mutagenesis, cell-based actin remodeling assay Structure High 18786395
2011 FHOD1 is a direct target of miR-200c. Knockdown of FHOD1 decreased expression and transcriptional activity of serum response factor (SRF) by interfering with translocation of the SRF coactivator MRTF-A, leading to downregulation of myosin light chain 2 (MLC2) expression and phosphorylation, impairing stress fiber formation and contractility. miR-200c modulation, siRNA knockdown, MRTF-A localization assay, SRF reporter assay, immunoblot for MLC2 Molecular and cellular biology Medium 22144583
2013 FHOD1 is recruited to integrin clusters in an early step of adhesion formation, resulting in actin assembly. FHOD1 knockdown impairs cell spreading, coordinated force application, and adhesion maturation. Targeting of FHOD1 to integrin sites depends on direct interaction with Src family kinases and is upstream of activation by Rho kinase. siRNA knockdown, spreading assays on lipid bilayers and solid substrates, high-resolution force-sensing pillar arrays, co-immunoprecipitation with Src family kinases Developmental cell High 24331927
2013 The formin FHOD1 and small GTPase Rac1 cooperate to promote vaccinia virus actin tail formation. FHOD1 depletion decreased CEV actin tail number and elongation rate. FHOD1 recruitment to actin tails requires its GTPase-binding domain and FH2 domain. Rac1 is activated at the membrane surrounding actin tails; Rac1 depletion or dominant-negative Rac1 phenocopies FHOD1 depletion and prevents FHOD1 recruitment. FHOD1 overexpression rescues actin tail defects from dominant-negative Rac1, placing FHOD1 downstream of Rac1. siRNA knockdown, dominant-negative Rac1 expression, FHOD1 domain truncation/rescue experiments, live imaging of actin tails The Journal of cell biology Medium 24062339
2013 Aurora-B kinase phosphorylates FHOD1; phosphomutant FHOD1 is impaired in post-mitotic assembly of oriented actin cables required for daughter cell spreading after cell division. APC/C(Cdh1) restricts a cell-cortex-associated pool of active Aurora-B in space and time, and Aurora-B retention at the cortex in early G1 depends on FHOD1. APC/C(Cdh1) manipulation, phospho-site identification in FHOD1, phosphomutant expression, immunofluorescence of actin cables and Aurora-B localization Journal of cell science Medium 23613471
2014 FHOD1 directly interacts with nesprin-2 giant (N2G), an outer nuclear membrane component. Silencing FHOD1 or expressing binding-domain fragments disrupts nuclear movement and centrosome orientation in polarizing fibroblasts. FHOD1 silencing does not affect formation or rearward flow of dorsal actin cables, but N2G-FHOD1 interaction provides a second attachment point to actin cables essential for TAN line formation and nuclear translocation. Co-immunoprecipitation, siRNA knockdown, dominant-negative fragment expression, live-cell imaging of nuclear movement, centrosome orientation assay Nature cell biology High 24880667
2014 FHOD1 controls stress fiber organization by differentially regulating two precursor populations: it inhibits dorsal fiber growth (which requires parallel long actin filament polymerization) while stimulating transverse arc formation (from fusion of short antiparallel filaments). The GBD and FH3 domains mediate stress fiber association and co-localization with myosin. FHOD1 lacking GBD/FH3 retains full capacity to stimulate arc and ventral stress fiber formation. siRNA knockdown, FHOD1 domain mutant expression, live-cell imaging, immunofluorescence for stress fiber subtypes and myosin Journal of cell science Medium 24481812
2014 FHOD1 is localized at intercalated discs and costameres in adult and neonatal cardiomyocytes, co-localizing with cadherin, plakoglobin, and connexin43 at the intercalated disc. N-terminal domain mediates subcellular targeting; constructs lacking this domain show aberrant localization. Confocal immunofluorescence, subcellular fractionation, immunoblot of isolated intercalated discs, expression of deletion constructs in neonatal cardiomyocytes Anatomical record Medium 25125170
2017 FHOD1 acts downstream of the LINC complex (lamin/nesprin-1) to mediate mechanosensing in muscle cell precursors. Pathogenic LMNA or SYNE-1 mutations cause excess contractile stress fibers, increased focal adhesions, and higher traction forces, all rescued by FHOD1 depletion or inactivation. ROCK inhibition prevents cytoskeletal defects, and FHOD1 is a ROCK-dependent effector placing it in the lamin/nesprin-1→ROCK→FHOD1 axis. Traction force microscopy, siRNA knockdown, ROCK inhibitor (Y-27632), patient-derived LMNA/SYNE-1 mutant cell lines, immunofluorescence Scientific reports Medium 28455503
2019 Active FHOD1 (C-terminal truncation) is recruited to all three types of actin stress fibers and is more incorporated with myosin II than α-actinin. Active FHOD1 emerges from the cell periphery and moves centripetally with transverse arcs. FHOD1 knockdown causes defective actomyosin bundle maturation with longer non-contractile dorsal stress fibers and slower actin centripetal flow, resulting in abnormal cell spreading and migration. FHOD1 truncation/active mutant expression, siRNA knockdown, live TIRF/confocal imaging of actin and myosin dynamics, FRAP for turnover measurements The Biochemical journal Medium 31657439
2021 Crystal structures of FHOD1 bound to nesprin-2G and nesprin-1G spectrin repeats (SRs) reveal that the presumed GBD of FHOD1 is actually a spectrin repeat-binding enhancer for the neighboring FH3 domain. SR binding by FHOD1 is likely not regulated by the DAD helix. Nesprin-1G also contains one FHOD1-binding SR, indicating overlapping functions of nesprins in actin-bundle recruitment for nuclear movement. X-ray crystallography, binding assays Structure High 33472039
2023 FHOD1 knockdown enhances ferroptosis sensitivity in glioma cells via upregulation of methylated HSPB1 (a negative regulator of ferroptosis). Overexpression of HSPB1 reverses FHOD1 knockdown-mediated ferroptosis, placing HSPB1 downstream of FHOD1 in ferroptosis regulation. siRNA knockdown, HSPB1 overexpression rescue, ferroptosis sensitivity assays, proteomics CNS neuroscience & therapeutics Low 37211949
2023 Activated FHOD1 promotes actin filament assembly and hypertrophy in vascular smooth muscle cells in response to Ang-II, and mediates hypertensive tunica media thickening in vivo. Activated FHOD1 or its C-terminal DAD domain upregulates RNF213 via stabilization of RNF213 protein (independent of G-actin/F-actin ratio, transcription, or translation), which in turn promotes collagen-1α/collagen-3α synthesis. In vivo hypertensive rat models, siRNA/overexpression in VSMCs, proteomics, collagen synthesis assays, FHOD1 phosphorylation analysis Journal of molecular and cellular cardiology Low 37482037
2024 PRMT7 methylates arginine residues (R1130/R1132 in FHOD1 DAD domain equivalent positions) in the diaphanous autoinhibitory domain of FHOD family proteins in vitro. If the adjacent serine (corresponding to Ser-1131 in FHOD1) is first phosphorylated by ROCK1, PRMT7 cannot subsequently methylate the neighboring arginines, indicating that phosphorylation and methylation at the DAD are mutually antagonistic PTMs. In vitro methylation assay with recombinant PRMT7, in vitro ROCK1 kinase assay, site-directed mutagenesis The Journal of biological chemistry Medium 39368550
2025 An in silico structural model (AlphaFold3) of the FHOD1 autoinhibitory complex (DID-DAD) indicates that an extended polybasic region unique to the FHOD subfamily stabilizes autoinhibitory interactions. Site-directed mutagenesis of polybasic region residues experimentally validates this prediction and confirms its role in autoinhibition and its disruption upon phosphorylation-dependent activation. AlphaFold3 structural modeling, site-directed mutagenesis, cell-based actin remodeling assay The Journal of biological chemistry Medium 41448430
2025 In 3D breast acini, FHOD1 is required for nuclear positioning and lumen formation downstream of nesprin-2G and SUN proteins. FHOD1 depletion disrupts a dynamic basal actin spot linking the nucleus to plasma membrane β1-integrin through the LINC complex and inhibits lumen formation. siRNA knockdown, 3D acini culture, live-cell imaging, nesprin-2 degron system, confocal microscopy bioRxivpreprint Low

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F. Molecular and cellular biology 205 22144583
2008 The mammalian formin FHOD1 is activated through phosphorylation by ROCK and mediates thrombin-induced stress fibre formation in endothelial cells. The EMBO journal 111 18239683
2014 FHOD1 interaction with nesprin-2G mediates TAN line formation and nuclear movement. Nature cell biology 100 24880667
2013 FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration. Developmental cell 90 24331927
2003 Activation of the Rac-binding partner FHOD1 induces actin stress fibers via a ROCK-dependent mechanism. The Journal of biological chemistry 85 12857739
2001 The formin/diaphanous-related protein, FHOS, interacts with Rac1 and activates transcription from the serum response element. The Journal of biological chemistry 79 11590143
2003 The formin-homology-domain-containing protein FHOD1 enhances cell migration. Journal of cell science 71 12665555
2008 The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing. The Journal of biological chemistry 60 18694941
2008 The human formin FHOD1 contains a bipartite structure of FH3 and GTPase-binding domains required for activation. Structure (London, England : 1993) 54 18786395
2013 FHOD1, a formin upregulated in epithelial-mesenchymal transition, participates in cancer cell migration and invasion. PloS one 53 24086398
2003 Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation. Journal of cell science 52 14576350
2014 FHOD1 regulates stress fiber organization by controlling the dynamics of transverse arcs and dorsal fibers. Journal of cell science 48 24481812
2005 Biochemical characterization of the diaphanous autoregulatory interaction in the formin homology protein FHOD1. The Journal of biological chemistry 46 16361249
2016 The Drosophila formin Fhos is a primary mediator of sarcomeric thin-filament array assembly. eLife 42 27731794
2017 Lamins and nesprin-1 mediate inside-out mechanical coupling in muscle cell precursors through FHOD1. Scientific reports 41 28455503
2005 FHOD1 coordinates actin filament and microtubule alignment to mediate cell elongation. Experimental cell research 35 15878344
2014 The Drosophila FHOD1-like formin Knittrig acts through Rok to promote stress fiber formation and directed macrophage migration during the cellular immune response. Development (Cambridge, England) 33 24553290
2013 The formin FHOD1 and the small GTPase Rac1 promote vaccinia virus actin-based motility. The Journal of cell biology 30 24062339
2004 Formin homology domain protein (FHOD1) is a cyclic GMP-dependent protein kinase I-binding protein and substrate in vascular smooth muscle cells. The Journal of biological chemistry 30 15051728
2012 SIRPα/CD172a and FHOD1 are unique markers of littoral cells, a recently evolved major cell population of red pulp of human spleen. Journal of immunology (Baltimore, Md. : 1950) 28 22490440
2013 Spatiotemporal organization of Aurora-B by APC/CCdh1 after mitosis coordinates cell spreading through FHOD1. Journal of cell science 26 23613471
2015 Reinforcing the LINC complex connection to actin filaments: the role of FHOD1 in TAN line formation and nuclear movement. Cell cycle (Georgetown, Tex.) 25 26083340
2004 EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21. Journal of cell science 24 15138285
2014 The formin FHOD1 in cardiomyocytes. Anatomical record (Hoboken, N.J. : 2007) 23 25125170
2018 Formin Proteins FHOD1 and INF2 in Triple-Negative Breast Cancer: Association With Basal Markers and Functional Activities. Breast cancer : basic and clinical research 22 30158824
2021 Structures of FHOD1-Nesprin1/2 complexes reveal alternate binding modes for the FH3 domain of formins. Structure (London, England : 1993) 19 33472039
2006 Caspase-3 cleaves the formin-homology-domain-containing protein FHOD1 during apoptosis to generate a C-terminal fragment that is targeted to the nucleolus. Apoptosis : an international journal on programmed cell death 19 17013756
2005 Oligomerization of the diaphanous-related formin FHOD1 requires a coiled-coil motif critical for its cytoskeletal and transcriptional activities. FEBS letters 19 15642356
2016 FHOD1 formin is upregulated in melanomas and modifies proliferation and tumor growth. Experimental cell research 18 27919746
2013 The role of the formin gene fhod-1 in C. elegans embryonic morphogenesis. Worm 17 24778933
2004 Identification of FHOD1-binding proteins and mechanisms of FHOD1-regulated actin dynamics. Journal of cellular biochemistry 17 15095401
2014 Distribution of formins in cardiac muscle: FHOD1 is a component of intercalated discs and costameres. European journal of cell biology 16 25555464
2017 FHOD1 regulates cytoplasmic actin-based spindle migration for mouse oocyte asymmetric cell division. Journal of cellular physiology 13 28708292
2023 FHOD1 is upregulated in glioma cells and attenuates ferroptosis of glioma cells by targeting HSPB1 signaling. CNS neuroscience & therapeutics 12 37211949
2020 FHOD-1 is the only formin in Caenorhabditis elegans that promotes striated muscle growth and Z-line organization in a cell autonomous manner. Cytoskeleton (Hoboken, N.J.) 12 33103378
2012 Fhos encodes a Drosophila Formin-like protein participating in autophagic programmed cell death. Genesis (New York, N.Y. : 2000) 12 22422652
2005 Src regulates the activity of the mammalian formin protein FHOD1. Biochemical and biophysical research communications 11 16169515
2019 Fhod1, an actin-organizing formin family protein, is dispensable for cardiac development and function in mice. Cytoskeleton (Hoboken, N.J.) 10 31008549
2024 FHOD-1 and profilin protect sarcomeres against contraction-induced deformation> in C. elegans. Molecular biology of the cell 9 39259762
2019 Active FHOD1 promotes the formation of functional actin stress fibers. The Biochemical journal 8 31657439
2005 The mammalian formin FHOD1 interacts with the ERK MAP kinase pathway. Biochemical and biophysical research communications 7 16112087
2021 FHOD1 is upregulated in gastric cancer and promotes the proliferation and invasion of gastric cancer cells. Oncology letters 6 34457067
2021 FHOD1 and FMNL1 formin proteins in intestinal gastric cancer: correlation with tumor-infiltrating T lymphocytes and molecular subtypes. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 5 34115237
2023 Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening. Journal of molecular and cellular cardiology 3 37482037
2023 Characterization of Expression and Function of the Formins FHOD1, INF2, and DAAM1 in HER2-Positive Breast Cancer. Journal of breast cancer 3 37985384
2007 Purification, crystallization and preliminary structural characterization of the N-terminal region of the human formin-homology protein FHOD1. Acta crystallographica. Section F, Structural biology and crystallization communications 2 17909294
2025 Role of FHOD1 in tumor cells and tumor immune microenvironment. Frontiers in immunology 1 40364836
2024 Methylation and phosphorylation of formin homology domain proteins (Fhod1 and Fhod3) by protein arginine methyltransferase 7 (PRMT7) and Rho kinase (ROCK1). The Journal of biological chemistry 1 39368550
2021 Downregulation of FHOD1 Inhibits Metastatic Potential in A549 Cells. Cancer management and research 1 33447082
2025 Structural basis underlying the autoinhibition of the formin FHOD1 and its phosphorylation-dependent activation. The Journal of biological chemistry 0 41448430

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