Affinage

CDC42

Cell division control protein 42 homolog · UniProt P60953

Length
191 aa
Mass
21.3 kDa
Annotated
2026-06-09
100 papers in source corpus 49 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC42 is a Rho-family GTP-binding protein and conserved molecular switch that cycles between membrane-associated active and cytosolic inactive states to govern actin-based morphogenesis, cell polarity, and intracellular trafficking (PMID:2122236, PMID:2124704, PMID:7891688). Its functional homology to yeast CDC42 was established by complementation, and its localization is controlled by C-terminal CAAX isoprenylation and GTP-stimulated carboxyl methylation that partition it between membranes and cytosol (PMID:2122236, PMID:2124704, PMID:2120220, PMID:1526984). The switch is regulated by a GAP that stimulates GTP hydrolysis on wild-type but not Val-12 CDC42 (PMID:1939135), by GEFs including Dbl, Ect2 and βPIX (PMID:1429634, PMID:15642749, PMID:21173111), and by RhoGDI, which binds prenylated CDC42 with high affinity through the Rho insert region to inhibit GDP dissociation and extract it from membranes, enabling cytosol–membrane cycling without being required for membrane targeting itself (PMID:1429634, PMID:9334181, PMID:8626553, PMID:11583574). In the GTP-bound state CDC42 engages a spectrum of effectors to drive distinct outputs: it triggers filopodia and peripheral actin microspikes (PMID:7891688), activates the serine kinases PAK and the CDC42-selective PAK4 and MRCK-α to control actin-myosin contractility and substrate phosphorylation (PMID:7744004, PMID:9822598, PMID:9418861, PMID:29295922), and recruits WASp–Arp2/3 to build actin-rich phagocytic cups and invadosome cores (PMID:11580754, PMID:24840388). Through IQGAP1 it integrates Ca2+/calmodulin signaling, sustains its own GTP-loaded state, and links to CLIP-170 to capture microtubules and establish polarized arrays (PMID:8670801, PMID:9867866, PMID:12110184, PMID:11948177). CDC42 establishes and maintains cell polarity via the Par6–aPKC complex and Arf6-dependent vesicular delivery to the leading edge, directing chemotactic steering through locally excitable GTPase gradients that antagonize RhoA and are shaped by the spatial distribution of GEFs (PMID:18319301, PMID:21173111, PMID:26689677, PMID:30446664, PMID:15684032). Beyond migration, CDC42 functions in epithelial and endothelial tubulogenesis and lumen formation, primary ciliogenesis via the exocyst component Sec10, mitotic kinetochore–microtubule attachment through Ect2/MgcRacGAP, Golgi positioning, and mTORC2/NDRG1-coupled mitochondrial fission (PMID:18319301, PMID:19914171, PMID:23766535, PMID:15642749, PMID:20525016, PMID:37386153). Missense variants that perturb the active/inactive switch or effector binding cause a clinically heterogeneous group of developmental disorders (PMID:29394990).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1990 High

    Established that the human G25K protein is a bona fide GTP-binding ortholog of yeast CDC42, defining it as a conserved molecular switch whose membrane association is set by lipid modification.

    Evidence cDNA cloning with yeast complementation and GTP-binding assays; metabolic [3H]mevalonate labeling with lovastatin inhibition and fractionation

    PMID:2120220 PMID:2122236 PMID:2124704

    Open questions at the time
    • Did not identify downstream effectors
    • Did not define which cellular processes the switch controls in human cells
  2. 1992 High

    Defined the regulatory inputs to the switch by purifying a CDC42-specific GAP and showing RhoGDI inhibits GDP dissociation and extracts CDC42 from membranes, framing the GEF/GAP/GDI control logic.

    Evidence Protein purification of platelet GAP with mutant specificity controls; GDP dissociation, membrane extraction, and carboxyl methylation assays with purified RhoGDI

    PMID:1429634 PMID:1526984 PMID:1939135

    Open questions at the time
    • GAP identity at the gene level not resolved here
    • Structural basis of GDI binding not yet defined
  3. 1995 High

    Connected active CDC42 to its cellular output, showing it drives filopodia formation and directly activates the PAK serine kinase in a GTP-dependent manner, establishing the GTPase-to-actin signaling axis.

    Evidence Microinjection of constitutively active and dominant-negative CDC42 with phalloidin imaging; purified PAK GTP-dependent binding and autophosphorylation/kinase assays

    PMID:7744004 PMID:7891688 PMID:8034624

    Open questions at the time
    • How PAK activation links to actin remodeling not fully traced
    • Did not establish the full effector repertoire
  4. 1996 High

    Identified IQGAP1/2 as effectors that bind GTP-CDC42 and inhibit its GTPase activity, and mapped the Rho insert region as the GDI-interaction determinant separable from effector binding, refining switch-state regulation.

    Evidence Affinity purification, reciprocal co-IP, GTPase assays, immunofluorescence; Cdc42/Ras chimera domain-swap mutagenesis; fluorescence-spectroscopy Kd determination

    PMID:8626553 PMID:8670801 PMID:8702968 PMID:9334181

    Open questions at the time
    • Functional consequence of IQGAP inhibition of GTP hydrolysis in cells unresolved
    • Insert-region role distinct from membrane targeting not yet tested
  5. 1998 High

    Expanded the effector network to CDC42-specific kinases and the actin nucleation machinery, defining how CDC42 produces distinct cytoskeletal and contractile outputs and drives phagocytosis.

    Evidence Co-IP and localization of PAK4 with kinase-dead/binding mutants; MRCK-α in vitro kinase assay on myosin light chain; dominant-negative CDC42 in FcgammaR phagocytosis with distinct morphological phenotypes

    PMID:9418861 PMID:9799231 PMID:9822598

    Open questions at the time
    • Spatial coordination of multiple effectors in one cell not resolved
    • Substrate specificity of MRCK-α versus PAK4 in vivo unclear
  6. 2001 High

    Demonstrated RhoGDI-dependent cytosol–membrane cycling and PAK-mediated phosphorylation of merlin, and tied CDC42-WASp-Arp2/3 to phagocytic cup actin assembly, mechanistically linking the switch to traffic, growth control, and engulfment.

    Evidence R66E GDI-binding-deficient mutant with fractionation/imaging; in vitro and in vivo PAK kinase assay on merlin Ser518; dominant-negative CDC42, WASp-KO, and Arp2/3 inhibition in phagocytosis

    PMID:11580754 PMID:11583574 PMID:11719502

    Open questions at the time
    • GDI cycling kinetics in living cells not measured
    • How GDI release is triggered physiologically not defined
  7. 2002 High

    Established CDC42 as a polarity organizer linking actin to microtubules via the IQGAP1–CLIP-170 tripartite complex, and showed IQGAP1 sustains the GTP-bound state, connecting effector binding to gradient maintenance.

    Evidence Co-IP of tripartite complex, GFP-CLIP-170 imaging, dominant-negative IQGAP1; IQGAP1 ΔGRD mutant with GTP-Cdc42 pulldown and filopodia readouts

    PMID:11948177 PMID:12110184

    Open questions at the time
    • How microtubule capture feeds back on CDC42 activity not resolved
    • Quantitative contribution of IQGAP1 to gradient steepness unknown
  8. 2005 High

    Visualized spatially patterned active-CDC42 zones and identified the mitotic Ect2/MgcRacGAP GEF/GAP pair, establishing that CDC42 functions through spatially confined activity and operates in mitosis as well as cortical remodeling.

    Evidence Active-GTPase biosensor imaging in wounded Xenopus oocytes with cytoskeletal/Ca2+ perturbation; RNAi and dominant-negative epistasis with GTP-Cdc42 pulldown and kinetochore imaging

    PMID:15642749 PMID:15684032

    Open questions at the time
    • Molecular basis of zone segregation from RhoA not defined
    • How mitotic GEF/GAP cycling is timed unresolved
  9. 2010 High

    Showed that polarized CDC42 activity during migration is established by Arf6-dependent vesicular delivery of CDC42/βPIX to the leading edge and that CDC42 controls microtubule-dependent Golgi positioning, coupling the switch to membrane trafficking.

    Evidence Live imaging of GFP-Cdc42 vesicles with Arf6 inhibition and polarity readouts; ARHGAP21 siRNA with Golgi repositioning and permeabilized-cell motility assays

    PMID:20525016 PMID:21173111

    Open questions at the time
    • How Arf6 traffic is spatially restricted not defined
    • Direct coatomer–CDC42 interaction at gene level not fully resolved
  10. 2013 High

    Defined in vivo developmental and disease roles—tubulogenesis, ciliogenesis via Sec10, YAP regulation—and linked germline CDC42 missense variants perturbing the switch to human developmental disorders.

    Evidence Tissue-specific conditional knockouts (pancreas, kidney) with polarity/YAP readouts; zebrafish cdc42/sec10 epistasis and co-IP; exome sequencing with in vitro GTPase/effector assays and animal models

    PMID:19914171 PMID:23555292 PMID:23766535 PMID:29394990

    Open questions at the time
    • Genotype-phenotype rules for variant classes incomplete
    • Tissue-specific effector usage not fully mapped
  11. 2018 High

    Resolved the structural basis of effector engagement, showing CDC42 binds PAK4 through an extended interface beyond the CRIB domain that modulates kinase activity and binding affinity.

    Evidence X-ray crystallography and SAXS of the full-length complex with kinase activity and affinity measurements

    PMID:29295922

    Open questions at the time
    • Whether other effectors use analogous extended interfaces unknown
    • In-cell relevance of the extended contacts not tested
  12. 2019 High

    Established CDC42 as a vascular morphogenesis regulator whose loss causes cavernous-malformation-like lesions via MEKK3-ERK5-KLF2/4 signaling, and identified CCM3 as a promoter of CDC42 activity.

    Evidence Inducible endothelial conditional knockout, retinal angiogenesis, signaling/western analysis, Klf4 co-KO rescue, CCM3–CDC42 co-IP

    PMID:30732528

    Open questions at the time
    • Mechanism by which CCM3 activates CDC42 not defined
    • How CDC42 loss elevates MEKK3 signaling not fully traced
  13. 2023 Medium

    Extended CDC42 function to organelle dynamics and identified novel upstream activators, implicating it in mTORC2/NDRG1-driven mitochondrial fission and in pTINCR/SUMO-dependent activation, and in tumor microvesicle shedding.

    Evidence Genetic epistasis, siRNA screens, proteomics and live imaging in Cdc42-deficient cells; co-IP and SUMOylation assays; MV shedding and EGFR internalization assays with mutants

    PMID:33473262 PMID:36369429 PMID:37386153

    Open questions at the time
    • Direct CDC42 effectors in mitochondrial fission not identified
    • These single-lab mechanisms await independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same CDC42 switch is allosterically partitioned in real time among its many effectors to specify distinct outputs (filopodia, polarity, mitosis, fission) within one cell remains unresolved.
  • No unified model linking spatial GTP-loading to effector selection
  • Quantitative effector competition in vivo not measured
  • Endogenous determinants of GDI release versus effector engagement undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 3 GO:0005829 cytosol 3 GO:0005929 cilium 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2
Partners
CCM3ECT2IQGAP1MRCK-ΑPAK4RHOGDISEC10WASP
Complex memberships
CDC42–RhoGDI heterodimerIQGAP1–CLIP-170 tripartite complexPar6–aPKC polarity complexWASp–Arp2/3

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 CDC42Hs (G25K) is the human homolog of yeast CDC42; the G25K cDNA encodes a 191-amino-acid GTP-binding protein that complements yeast cdc42-1 and cdc24-4 temperature-sensitive lethal mutations, demonstrating functional conservation. cDNA cloning, yeast complementation assay, GTP-binding assay Molecular and cellular biology High 2122236 2124704
1990 CDC42Hs (G25K) undergoes isoprenoid (farnesyl) modification at its C-terminal CAAX motif, and this modification regulates its association with cell membranes versus cytosol. Metabolic labeling with [3H]mevalonate, 2D gel electrophoresis, immunoblotting, lovastatin inhibition, subcellular fractionation The Journal of biological chemistry High 2120220
1991 A GTPase-activating protein (GAP) for CDC42Hs was purified from human platelets; it stimulates GTP hydrolysis on wild-type CDC42Hs but not on the Val-12 mutant, and shows weak cross-reactivity with Rho but not with Ras or Rap. Protein purification (~3500-fold), GTPase activity assay, mutant specificity analysis The Journal of biological chemistry High 1939135
1992 Rho-GDI (GDP-dissociation inhibitor) inhibits GDP dissociation from CDC42Hs and stimulates release of CDC42Hs from plasma membranes. The purified brain GDI also inhibits Dbl-catalyzed GDP dissociation from CDC42Hs. Protein purification, GDP dissociation assay, membrane extraction assay, immunoblotting The Journal of biological chemistry High 1429634
1992 CDC42Hs (G25K) undergoes GTP-stimulated carboxyl methylation in brain; it exists as a heterodimer with a 28-kDa protein (RhoGDI), and the associated GDI decreases methylation efficiency and alters guanine nucleotide specificity. Protein purification, carboxyl methylation assay, two-dimensional electrophoresis, subcellular fractionation The Journal of biological chemistry Medium 1526984
1994 GTP-bound CDC42Hs directly associates with the p85 subunit of PI 3-kinase via the Rho-GAP homology domain of p85, and this interaction stimulates PI 3-kinase activity 2–4-fold; the effector domain mutant T35A abolishes binding. GST pulldown with purified recombinant proteins, co-immunoprecipitation from cell lysates, PI 3-kinase activity assay, effector-domain mutant analysis The Journal of biological chemistry High 8034624
1995 Microinjection of constitutively active CDC42Hs into Swiss 3T3 fibroblasts induces peripheral actin microspikes and filopodia; bradykinin activates endogenous CDC42Hs to produce the same effects, which are blocked by dominant-negative CDC42Hs(T17N). Microinjection, phalloidin staining, time-lapse phase-contrast microscopy, dominant-negative inhibition Molecular and cellular biology High 7891688
1995 PAK (hPAK65) is a serine kinase that binds Rac1 and CDC42Hs in a GTP-dependent manner; GTP-bound CDC42Hs or Rac1 induces autophosphorylation of PAK on serine residues, which activates its kinase activity toward myelin basic protein independently of continued GTPase binding. Protein purification from neutrophil cytosol, GTP-dependent binding assay, in vitro autophosphorylation assay, kinase activity assay toward exogenous substrate The EMBO journal High 7744004
1995 CDC42Hs translocates from the membrane skeleton to the cytoskeleton in platelets stimulated by TRAP or ADP; this translocation is mediated by αIIbβ3 integrin activation and requires actin polymerization and protein-tyrosine kinase activity. Subcellular fractionation, immunoblotting, cytochalasin and genistein inhibition, integrin blockade The Journal of biological chemistry Medium 7542236
1996 IQGAP1 (p195) is a CDC42Hs effector: it binds preferentially to GTP-bound CDC42Hs and Rac, inhibits CDC42Hs GTPase activity, and co-immunoprecipitates with CDC42Hs from cell lysates. IQGAP1 localizes to lamellipodia and ruffles where it co-localizes with actin. Affinity chromatography (GTP-Cdc42Hs bead purification), GTPase activity assay, co-immunoprecipitation, immunofluorescence, yeast CDC42/CDC24 pathway inhibition assay The EMBO journal High 8670801
1996 IQGAP2 (p175) interacts with CDC42Hs in a manner that is less nucleotide-dependent than IQGAP1; both IQGAP1 and IQGAP2 require the switch I domain and an insert region unique to Rho-family proteins for CDC42Hs binding. Protein purification from rabbit liver cytosol, pulldown with GTP/GDP-Cdc42Hs, chimeric mutant analysis, microsequencing The Journal of biological chemistry Medium 8702968
1996 The Rho insert region (residues 122–134) of CDC42Hs is required for RhoGDI-mediated inhibition of GDP dissociation and GTP hydrolysis, and for GDI-stimulated membrane release; this region is not required for effector (PAK, GEF Dbl, or GAP) interactions. Cdc42Hs/Ha-Ras chimeric mutant construction, GDP dissociation assay, GTPase activity assay, membrane release assay, effector binding assay The Journal of biological chemistry High 9334181
1996 RhoGDI binds GDP- and GTP-bound CDC42Hs with similar affinity (~30 nM Kd) as measured by direct fluorescence spectroscopy; the carboxyl-terminal domain of GDI confers high-affinity binding; prenylation of CDC42Hs is required for GDI-induced fluorescence quenching. Fluorescence spectroscopy using Mant-GDP-loaded CDC42Hs, binding titration, GDI/LD4 chimera analysis, truncation mutants The Journal of biological chemistry High 8626553
1997 Dominant-negative CDC42Hs(T17N) inhibits serum-stimulated cell cycle progression at G1/S in a p38-dependent manner, but Rac1 dominant negative does not produce the same block, demonstrating a specific and distinct role for CDC42Hs in cell cycle inhibition via the p38 pathway. Quantitative microinjection of dominant-negative GTPases into fibroblasts, cell cycle analysis, pharmacological inhibition of p38 The Journal of biological chemistry Medium 9148940
1997 The CDC42Hs(F28L) fast-cycling mutant (which undergoes spontaneous GTP-GDP exchange while retaining GTPase activity) activates JNK1, induces filopodia, and causes oncogenic transformation including anchorage-independent growth and reduced contact inhibition. Site-directed mutagenesis, JNK reporter assays, filopodia formation by immunofluorescence, focus formation and soft-agar growth assays Current biology : CB Medium 9368762
1998 PAK4 is a CDC42Hs-specific effector kinase that interacts with activated CDC42Hs via its GBD; co-expression of PAK4 and constitutively active CDC42Hs redistributes PAK4 to the Golgi and induces filopodia and actin polymerization in a manner dependent on PAK4 kinase activity and CDC42Hs binding. Co-immunoprecipitation, immunofluorescence localization, kinase-dead and binding-deficient mutant analysis, brefeldin A treatment, actin staining The EMBO journal High 9822598
1998 MRCK-α (myotonic dystrophy kinase-related Cdc42-binding kinase) binds GTP-Cdc42 through a PAK-like p21-binding domain and phosphorylates non-muscle myosin light chain at Ser19, driving actin-myosin contractility; kinase-dead MRCK-α blocks Cdc42V12-dependent peripheral microspikes and focal complexes. Recombinant protein binding assay, in vitro kinase assay (myosin light chain phosphorylation), microinjection, kinase-dead and Cdc42-binding-deficient mutants, immunofluorescence Molecular and cellular biology High 9418861
1998 Dominant-negative forms of both Rac1 and CDC42 inhibit Fcγ receptor-mediated phagocytosis in macrophages, but with distinct phenotypes: CDC42 inhibition produces pedestal-like structures while Rac1 inhibition traps particles in thin membrane protrusions, indicating cooperative but distinct roles in phagocytic cup assembly. Stable transfection of dominant-negative GTPases in RBL-2H3 cells, F-actin staining, particle internalization assay, Clostridium difficile toxin B inhibition The EMBO journal High 9799231
1998 Integrin-dependent adhesion to fibronectin activates CDC42 (and Rac1), as evidenced by activation of the downstream effector PAK; dominant-negative CDC42 inhibits cell spreading, and epistasis experiments indicate integrins activate CDC42 first, which then activates Rac1 to drive spreading. PAK activation assay (downstream readout), dominant-negative GTPase expression, cell spreading assay on fibronectin Molecular biology of the cell Medium 9658176
1999 IQGAP1 integrates Ca2+/calmodulin and CDC42 signaling: in the absence of Ca2+, IQGAP1 binds GTP-Cdc42 and inhibits its GTPase activity; Ca2+/calmodulin dissociates Cdc42 from IQGAP1 and restores GTP hydrolysis. Calmodulin binds the IQ motifs and calponin homology domain of IQGAP1; F-actin competes with Ca2+/calmodulin for the calponin homology domain. In vitro GTPase activity assay, in vitro binding assay, cell lysate co-immunoprecipitation, Ca2+ titration The Journal of biological chemistry High 9867866
2000 Active CDC42Hs and Rac1 GTPases cause perinuclear collapse of the vimentin intermediate filament network; this effect is independent of CRIB-mediated (PAK/JNK) pathways but is associated with actin reorganization and requires tyrosine phosphorylation events. Expression of activated GTPases and effector-loop mutants, immunofluorescence of vimentin, pharmacological inhibition (genistein, staurosporin, cytochalasin D), phosphorylation analysis The Journal of biological chemistry Medium 10900195
2001 p21-activated kinase (PAK) phosphorylates merlin (NF2 tumor suppressor) at serine 518 downstream of activated Rac and CDC42; both in vivo (cell-based) and in vitro kinase assays confirmed direct PAK-mediated phosphorylation of merlin. In vitro kinase assay, in vivo kinase assay in cells, expression of activated Rac and Cdc42, site-directed analysis (Ser518) The Journal of biological chemistry High 11719502
2001 RhoGDI is required for cycling of CDC42Hs between membranes and cytosol: a CDC42Hs R66E mutant defective in RhoGDI binding is found exclusively in membrane fractions (predominantly Golgi), whereas wild-type CDC42Hs redistributes to the cytosol when RhoGDI is overexpressed; RhoGDI binding is not required for membrane targeting or filopodia induction. Site-directed mutagenesis (R66E), subcellular fractionation, immunofluorescence, RhoGDI overexpression The Biochemical journal High 11583574
2001 During invasin/β1-integrin-mediated phagocytosis in macrophages, CDC42Hs activates WASp and the Arp2/3 complex to drive actin-rich phagocytic cup formation; dominant-negative CDC42Hs, WASp-knockout, and Arp2/3 inhibition each block cup formation and uptake. Microinjection of dominant-negative N17CDC42Hs, WASp-KO macrophages, Arp2/3 inhibitor microinjection, F-actin staining, internalization assay Cellular microbiology High 11580754
2001 CDC42Hs facilitates cytoskeletal reorganization and neurite outgrowth through the adaptor protein IRS-58 (58-kDa insulin receptor substrate); an IRS-58 mutant unable to bind CDC42Hs (I267N) fails to localize to F-actin and cannot induce filopodia or neurite outgrowth. Yeast two-hybrid, immunofluorescence co-localization, loss-of-function mutant (I267N), neurite outgrowth assay The Journal of cell biology Medium 11157984
2002 Active Rac1 and CDC42 form a tripartite complex with IQGAP1 and CLIP-170; IQGAP1 acts as the physical link between active CDC42/Rac1 and CLIP-170 at microtubule tips, thereby capturing microtubules at the leading edge to establish a polarized array and cell polarization. Co-immunoprecipitation, GFP-CLIP-170 imaging, dominant-negative IQGAP1 expression, microtubule array analysis Cell High 12110184
2002 IQGAP1 maintains CDC42 in the GTP-bound active state by inhibiting its GTPase activity; an IQGAP1 deletion mutant lacking part of the GAP-related domain (IQGAP1ΔGRD) increases intrinsic GTPase activity of CDC42 and blocks bradykinin-induced CDC42 activation, membrane translocation, and filopodia formation. IQGAP1 overexpression and ΔGRD mutant transfection, GTP-Cdc42 pulldown from cell lysates, in vitro GTPase assay, subcellular fractionation, filopodia scoring The Journal of biological chemistry High 11948177
2003 Activated CDC42 binds p85Cool-1/β-Pix, which directly associates with c-Cbl ubiquitin ligase, thereby preventing c-Cbl from binding the EGF receptor and catalyzing its ubiquitination; constitutively active CDC42(F28L) causes aberrant EGFR accumulation and sustained ERK activation leading to cellular transformation. Co-immunoprecipitation, ubiquitination assay, EGFR degradation assay, ERK activation assay, transformation assays Cell High 14505571
2005 In Xenopus oocyte wound healing, active CDC42 and active RhoA form distinct concentric zones around wound sites in a calcium-dependent manner; CDC42 occupies the middle of the F-actin array while RhoA is interior; these zones form before F-actin accumulation, require microtubules and F-actin, and depend on RhoA–CDC42 crosstalk. Fluorescence biosensor imaging (active CDC42/RhoA reporters) in wounded Xenopus oocytes, microtubule/actin depolymerization, Ca2+ chelation The Journal of cell biology High 15684032
2005 In mitosis, Ect2 (GEF) and MgcRacGAP activate and then inactivate CDC42, respectively, to elevate GTP-CDC42 in metaphase; this CDC42 activation is required for proper kinetochore–microtubule attachment, chromosome alignment, and segregation. RNAi depletion of Ect2 and Cdc42, dominant-negative mutant expression, GTP-Cdc42 pulldown assay, immunofluorescence of spindle/kinetochores The Journal of cell biology High 15642749
2005 Secramine inhibits CDC42 activation by a mechanism dependent on RhoGDI: it inhibits CDC42 membrane binding, GTP loading, and effector binding in a RhoGDI-dependent manner in vitro, and mimics dominant-negative CDC42 effects on Golgi protein export and polarization in cells. In vitro GTP-binding assay, membrane binding assay, effector binding assay with and without RhoGDI, RhoGDI-dependence experiments, cell-based Golgi traffic assay Nature chemical biology High 16408091
2008 CDC42 and Rac1 drive endothelial lumen formation in 3D collagen matrices through downstream effectors Pak2, Pak4, Par3, Par6, and PKCε/ζ; RNAi knockdown of Pak2 or Pak4 markedly inhibits lumen formation, and disruption of the Cdc42–Par3–Par6–PKCζ polarity complex impairs lumenogenesis. RNAi knockdown, dominant-negative expression, 3D collagen matrix lumenogenesis assay, Pak phosphorylation assays Journal of cell science High 18319301
2009 CDC42 is essential for pancreatic tubulogenesis specifically for initiating microlumen formation and maintaining apical cell polarity; Cdc42 controls cell specification non-cell-autonomously by providing a correct microenvironment for multipotent progenitor fate choices. Conditional knockout in pancreatic lineage (mouse), histology, immunofluorescence of polarity markers, lineage tracing Cell High 19914171
2010 During directed cell migration, CDC42 (with its exchange factor βPIX) localizes to intracytoplasmic vesicles and is recruited to the leading edge via Arf6-dependent membrane trafficking; inhibiting Arf6-dependent traffic abolishes polarized CDC42 and βPIX recruitment, Par6-aPKC complex polarization, and directed migration. Live-cell imaging of GFP-Cdc42-positive vesicles, Arf6 inhibition, immunofluorescence, cell polarization assay The Journal of cell biology High 21173111
2010 CDC42 regulates microtubule-dependent Golgi positioning; ARHGAP21 (Cdc42-specific GAP) knockdown inhibits Golgi repositioning to the centrosome; disrupting Cdc42 activation or the coatomer/Cdc42 binding interaction stimulates dynein-dependent Golgi motility, placing Cdc42 downstream of ARF1 and coatomer in regulating Golgi capture. siRNA knockdown of ARHGAP21, nocodazole washout Golgi repositioning assay, Golgi capture and motility assay in permeabilized cells, dynein inhibitory antibody Traffic (Copenhagen, Denmark) Medium 20525016
2013 Missense variants in CDC42 variably perturb its switch between active/inactive states and/or its interaction with effectors, causing a clinically heterogeneous group of developmental disorders; in vitro functional assays confirmed altered GTPase activity and effector binding for specific mutants. Exome sequencing, in silico analysis, in vitro GTPase activity assay, effector-binding assays, in vivo zebrafish/animal models American journal of human genetics Medium 29394990
2013 CDC42 is required for primary ciliogenesis: CDC42 co-localizes with the exocyst component Sec10 at primary cilia, interacts with Sec10, and its knockout in kidney tubular epithelial cells causes ciliogenesis defects, cystogenesis, and MAPK activation; zebrafish cdc42 and sec10 show synergistic genetic interaction in the same pathway. Morpholino knockdown in zebrafish (genetic interaction), conditional knockout in mouse kidney, immunofluorescence (co-localization), co-IP (Sec10 interaction), MAPK assay Journal of the American Society of Nephrology : JASN High 23766535
2013 CDC42 conditional knockout in the nephrogenic lineage phenocopies Yap loss; ablation of CDC42 decreases nuclear localization of YAP and reduces YAP-dependent gene expression, placing CDC42 upstream of YAP nuclear translocation in nephron progenitor cells. Conditional knockout (mouse), microarray, immunofluorescence of YAP localization, gene expression analysis PLoS genetics Medium 23555292
2013 A novel allosteric CDC42-selective inhibitor (identified by HTS) acts as a noncompetitive inhibitor with no activity toward Rho or Rac; it inhibits CDC42-related filopodia formation and cell migration in cells, demonstrating that allosteric inhibition of nucleotide binding is feasible for selectively targeting CDC42. High-throughput screening, GTPase biochemical assay, structure-activity relationship, filopodia formation assay, cell migration assay The Journal of biological chemistry Medium 23382385
2013 Active CDC42 is both necessary and sufficient to form invadosome actin cores in multiple cell types; combined with Tks5 expression, CDC42-driven actin cores acquire proteolytic activity, defining a minimal molecular signature of invadosomes. Overexpression of constitutively active Cdc42, Tks5 co-expression, immunofluorescence, gelatin degradation assay Cell adhesion & migration Medium 24840388
2015 During chemotaxis, local CDC42 signals (but not Rac, RhoA, or Ras signals) precede and predict cell turning; CDC42 has excitable properties (recurring local activity pulses revealed upon actin inhibition) and antagonizes RhoA, maintaining a steep spatial activity gradient that directs chemotactic steering. Fluorescence biosensors (FRET/FLIM) in neutrophil-like PLB-985 cells, photorelease of chemoattractant, actin polymerization inhibition, GTPase activity imaging Nature cell biology High 26689677
2017 CDC42 activity is required for optogenetically induced cell turning; the shape of the Cdc42 gradient is set by the spatial distribution of GEFs, not by transport, with a steep Cdc42 gradient maximizing directionality; a GAP (β2-chimaerin, localized at the cell tip by Cdc42 and Rac1 feedbacks) shapes the Rac1 gradient. Optogenetics (photoactivatable Rac1/Cdc42), micropatterned GEF substrates, FRET biosensors, live-cell imaging Nature communications High 30446664
2017 Cytoplasmic YAP positively regulates CDC42 activity in endothelial cells; CDC42 deletion causes severe defects in endothelial cell migration during retinal angiogenesis, and overexpression of cytoplasmic YAP (YAPS127D) partially rescues Yap/Taz-deficient migration defects through CDC42. Conditional knockout (endothelial-specific Yap/Taz and Cdc42), rescue with YAPS127D, retinal angiogenesis assay, GTPase activity assay Proceedings of the National Academy of Sciences of the United States of America Medium 28973878
2018 CDC42 binds PAK4 through an extended interface beyond the canonical CRIB domain, including additional contacts between the PAK4 kinase C-lobe, CDC42, and the PAK4 polybasic region; these additional contacts modulate kinase activity and increase CDC42 binding affinity compared to CRIB domain alone. X-ray crystallography, solution scattering (SAXS), kinase activity assay, binding affinity measurement Proceedings of the National Academy of Sciences of the United States of America High 29295922
2019 Endothelial-specific deletion of CDC42 elicits cerebrovascular malformations resembling cerebral cavernous malformations (CCM) by increasing MEKK3-MEK5-ERK5 signaling and overexpression of KLF2 and KLF4; co-inactivation of Klf4 reduces malformation severity; CDC42 interacts with CCM proteins, and CCM3 promotes CDC42 activity in endothelial cells. Inducible endothelial-specific conditional knockout (mouse), retinal angiogenesis assay, signaling pathway analysis (western blot), genetic rescue (Klf4 co-KO), co-immunoprecipitation (CCM3–CDC42) Circulation research High 30732528
2021 Activated GTP-bound CDC42 and its effector IQGAP1 are required for tumor microvesicle (MV) shedding; activated CDC42 also prevents EGFR internalization to maintain sustained EGF signaling that facilitates MV release, and blocking CDC42 signaling reduces MV-promoted tumor angiogenesis in vivo. Co-immunoprecipitation (CDC42–IQGAP1), dominant-negative and constitutively active mutants, MV shedding assay, EGFR internalization assay, in vivo tumor angiogenesis assay Journal of extracellular vesicles Medium 33473262
2022 The microprotein pTINCR binds to CDC42 and promotes CDC42 SUMOylation and activation, triggering a pro-differentiation cascade in epithelial cells; this places pTINCR as a positive upstream regulator of CDC42 activity via a SUMO-dependent mechanism. Co-immunoprecipitation (pTINCR–CDC42), SUMOylation assay, gain- and loss-of-function studies, in vitro differentiation assay, patient-derived xenograft Nature communications Medium 36369429
2023 mTORC2 phosphorylates NDRG1 at Ser336 during fasting, and phosphorylated NDRG1 cooperates with CDC42 and its effectors/regulators to orchestrate mitochondrial fission; Cdc42-deficient cells display fission failure phenotypes similar to NDRG1-Ser336Ala mutants and RictorKO cells. Time-lapse imaging, siRNA screen, epistasis experiments, proteomics, Cdc42-deficient cells (genetic), phosphorylation-deficient mutants Nature cell biology Medium 37386153

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Molecular and cellular biology 880 7891688
2004 Cdc42--the centre of polarity. Journal of cell science 599 15020669
1998 Activation of Rac and Cdc42 by integrins mediates cell spreading. Molecular biology of the cell 536 9658176
2002 Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 503 12110184
2001 Rho and Rac but not Cdc42 regulate endothelial cell permeability. Journal of cell science 392 11257000
1994 Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. The Journal of biological chemistry 346 8034624
1997 Requirements for both Rac1 and Cdc42 in membrane ruffling and phagocytosis in leukocytes. The Journal of experimental medicine 343 9348306
1996 IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. The EMBO journal 342 8670801
1995 A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. The EMBO journal 327 7744004
1998 PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. The EMBO journal 309 9822598
2005 Concentric zones of active RhoA and Cdc42 around single cell wounds. The Journal of cell biology 279 15684032
2013 Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development. PLoS genetics 251 23555292
1998 Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization. Molecular and cellular biology 233 9418861
2001 p21-activated kinase links Rac/Cdc42 signaling to merlin. The Journal of biological chemistry 218 11719502
2018 Targeting Rac and Cdc42 GTPases in Cancer. Cancer research 204 29858187
2009 Cdc42-mediated tubulogenesis controls cell specification. Cell 202 19914171
1998 Fc receptor-mediated phagocytosis requires CDC42 and Rac1. The EMBO journal 199 9799231
2011 Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cellular signalling 197 21515363
1990 Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42. Proceedings of the National Academy of Sciences of the United States of America 197 2124704
1997 A novel Cdc42Hs mutant induces cellular transformation. Current biology : CB 195 9368762
1999 IQGAP1 integrates Ca2+/calmodulin and Cdc42 signaling. The Journal of biological chemistry 192 9867866
2003 Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell 167 14505571
1998 The p21Rac/Cdc42-activated kinases (PAKs). The international journal of biochemistry & cell biology 167 9744077
1997 Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. The Journal of biological chemistry 167 9148940
2008 Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. Journal of cell science 164 18319301
2017 YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proceedings of the National Academy of Sciences of the United States of America 163 28973878
2018 Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes. American journal of human genetics 153 29394990
1992 The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein. The Journal of biological chemistry 153 1429634
2010 Cdc42 and vesicle trafficking in polarized cells. Traffic (Copenhagen, Denmark) 151 20633244
2010 Signaling role of Cdc42 in regulating mammalian physiology. The Journal of biological chemistry 147 21115489
2010 Cdc42 localization and cell polarity depend on membrane traffic. The Journal of cell biology 143 21173111
1990 Molecular cloning and expression of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42. Molecular and cellular biology 143 2122236
2001 Cdc42Hs facilitates cytoskeletal reorganization and neurite outgrowth by localizing the 58-kD insulin receptor substrate to filamentous actin. The Journal of cell biology 140 11157984
2015 Locally excitable Cdc42 signals steer cells during chemotaxis. Nature cell biology 139 26689677
2002 IQGAP1 is a component of Cdc42 signaling to the cytoskeleton. The Journal of biological chemistry 135 11948177
1998 RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs. Molecular biology of the cell 135 9614181
2013 Characterization of a Cdc42 protein inhibitor and its use as a molecular probe. The Journal of biological chemistry 134 23382385
1996 Identification of a putative effector for Cdc42Hs with high sequence similarity to the RasGAP-related protein IQGAP1 and a Cdc42Hs binding partner with similarity to IQGAP2. The Journal of biological chemistry 132 8702968
2013 Daughter cell identity emerges from the interplay of Cdc42, septins, and exocytosis. Developmental cell 125 23906065
2005 Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro. Nature chemical biology 123 16408091
2003 IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton. FEBS letters 115 12729888
2008 Cellular signaling for activation of Rho GTPase Cdc42. Cellular signalling 113 18558478
1996 Characterization of the interaction between RhoGDI and Cdc42Hs using fluorescence spectroscopy. The Journal of biological chemistry 106 8626553
1998 Chp, a homologue of the GTPase Cdc42Hs, activates the JNK pathway and is implicated in reorganizing the actin cytoskeleton. Current biology : CB 103 9778532
2000 Critical activities of Rac1 and Cdc42Hs in skeletal myogenesis: antagonistic effects of JNK and p38 pathways. Molecular biology of the cell 99 10930450
2002 GTPase-activating proteins for Cdc42. Eukaryotic cell 97 12455995
2005 Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis. The Journal of cell biology 93 15642749
2020 Targeting Rac and Cdc42 GEFs in Metastatic Cancer. Frontiers in cell and developmental biology 92 32322580
2005 Rac1/Cdc42 and RhoA GTPases antagonistically regulate chondrocyte proliferation, hypertrophy, and apoptosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 90 15883643
2019 Regulation of Cdc42 and its effectors in epithelial morphogenesis. Journal of cell science 86 31113848
2015 Cdc42: Role in Cancer Management. Chemical biology & drug design 86 25777055
2009 IQGAP1 regulates cell proliferation through a novel CDC42-mTOR pathway. Journal of cell science 71 19454477
2001 Yersinia enterocolitica invasin triggers phagocytosis via beta1 integrins, CDC42Hs and WASp in macrophages. Cellular microbiology 71 11580754
2015 Cdc42 and Cellular Polarity: Emerging Roles at the Golgi. Trends in cell biology 70 26704441
2013 Cdc42 deficiency causes ciliary abnormalities and cystic kidneys. Journal of the American Society of Nephrology : JASN 70 23766535
2011 Cdc42: an important regulator of neuronal morphology. The international journal of biochemistry & cell biology 70 22172377
1999 Signalling to actin: the Cdc42-N-WASP-Arp2/3 connection. Chemistry & biology 70 10467124
1990 Isoprenoid modification of G25K (Gp), a low molecular mass GTP-binding protein distinct from p21ras. The Journal of biological chemistry 68 2120220
2013 Targeting Cdc42 in cancer. Expert opinion on therapeutic targets 67 23957315
2018 Optogenetic dissection of Rac1 and Cdc42 gradient shaping. Nature communications 62 30446664
2000 Cdc42Hs and Rac1 GTPases induce the collapse of the vimentin intermediate filament network. The Journal of biological chemistry 62 10900195
1991 Identification of the human platelet GTPase activating protein for the CDC42Hs protein. The Journal of biological chemistry 62 1939135
2015 Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1. Small GTPases 58 26090570
2005 Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. Journal of cell science 57 15728253
1998 CDC42 and FGD1 cause distinct signaling and transforming activities. Molecular and cellular biology 55 9671479
2004 Regulation of anoikis by Cdc42 and Rac1. Experimental cell research 54 15093747
2006 Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. The Journal of biological chemistry 53 17038317
2017 Polarity establishment by Cdc42: Key roles for positive feedback and differential mobility. Small GTPases 51 28350208
1997 Interaction between Cdc42Hs and RhoGDI is mediated through the Rho insert region. The Journal of biological chemistry 47 9334181
1995 Integrin alpha IIb beta 3-mediated translocation of CDC42Hs to the cytoskeleton in stimulated human platelets. The Journal of biological chemistry 46 7542236
2019 CDC42 Deletion Elicits Cerebral Vascular Malformations via Increased MEKK3-Dependent KLF4 Expression. Circulation research 44 30732528
2019 CDC42 promotes vascular calcification in chronic kidney disease. The Journal of pathology 43 31397884
2016 The Borg family of Cdc42 effector proteins Cdc42EP1-5. Biochemical Society transactions 43 27913681
2012 hnRNP Q regulates Cdc42-mediated neuronal morphogenesis. Molecular and cellular biology 43 22493061
2023 mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission. Nature cell biology 42 37386153
2022 pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation. Nature communications 42 36369429
2021 Progress in the therapeutic inhibition of Cdc42 signalling. Biochemical Society transactions 41 34100887
2016 Cdc42 in actin dynamics: An ordered pathway governed by complex equilibria and directional effector handover. Small GTPases 40 27715449
2015 Distinct predictive performance of Rac1 and Cdc42 in cell migration. Scientific reports 40 26634649
1992 GTP-stimulated carboxyl methylation of a soluble form of the GTP-binding protein G25K in brain. The Journal of biological chemistry 40 1526984
2020 Regulation of Cdc42 for polarized growth in budding yeast. Microbial cell (Graz, Austria) 38 32656257
2014 Cdc42 and Tks5: a minimal and universal molecular signature for functional invadosomes. Cell adhesion & migration 36 24840388
2018 Phosphatidylserine and GTPase activation control Cdc42 nanoclustering to counter dissipative diffusion. Molecular biology of the cell 35 29668348
2014 Cdc42 GTPase dynamics control directional growth responses. Proceedings of the National Academy of Sciences of the United States of America 35 24385582
2000 Extinction of rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway. Oncogene 35 10828879
2021 Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis. Journal of extracellular vesicles 34 33473262
2015 Essential roles of Cdc42 and MAPK in cadmium-induced apoptosis in Litopenaeus vannamei. Aquatic toxicology (Amsterdam, Netherlands) 34 25863597
2014 CDC-42 and RAC-1 regulate opposite chemotropisms in Neurospora crassa. Journal of cell science 34 24790223
2017 Scaffold-mediated gating of Cdc42 signalling flux. eLife 33 28304276
2010 Cdc42 regulates microtubule-dependent Golgi positioning. Traffic (Copenhagen, Denmark) 33 20525016
2018 CDC42 binds PAK4 via an extended GTPase-effector interface. Proceedings of the National Academy of Sciences of the United States of America 32 29295922
2017 FMNL2 and -3 regulate Golgi architecture and anterograde transport downstream of Cdc42. Scientific reports 32 28852060
2000 SPECs, small binding proteins for Cdc42. The Journal of biological chemistry 32 10816584
1998 Identification of the binding surface on Cdc42Hs for p21-activated kinase. Biochemistry 32 9760238
2016 Cdc42 regulates Cdc42EP3 function in cancer-associated fibroblasts. Small GTPases 31 27248291
2015 CDC42 Use in Viral Cell Entry Processes by RNA Viruses. Viruses 31 26690467
2007 Spatial regulation of Cdc42 during cytokinesis. Cell cycle (Georgetown, Tex.) 31 17637568
2021 Molecular subversion of Cdc42 signalling in cancer. Biochemical Society transactions 30 34196668
2015 Effects of CDC42 on the proliferation and invasion of gastric cancer cells. Molecular medicine reports 30 26549550
2001 RhoGDI-binding-defective mutant of Cdc42Hs targets to membranes and activates filopodia formation but does not cycle with the cytosol of mammalian cells. The Biochemical journal 30 11583574

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