Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue

Pasteris, N. German; Nagata, Koh‐ichi; Hall, Alan; Gorski, Jerome L.

doi:10.1016/s0378-1119(99)00518-1

Cited by 41 publications

(46 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of FGD2 led to elevated levels of active GTP-bound Cdc42, and FGD2 activated JNK1 activity when expressed with Cdc42, but not Rac1, consistent with Cdc42 specificity. FGD1, FGD3, and FGD4 (Frabin) are known to activate Cdc42 directly (17)(18)(19), we presume the same to be true for FGD2, although so far, we have been unable to generate a soluble recombinant FGD2 that contains any exchange activity in vitro.…”

Section: Discussionmentioning

confidence: 89%

“…Studies have demonstrated that FGD1 is a guanine nucleotide exchange factor for the GTPase Cdc42, which plays important roles in cytoskeletal regulation and the organization of actin filaments (16,17). FGD3 and FGD4 have also been shown to modulate the actin cytoskeleton and to be Cdc42-specific exchange factors (18,19). Interestingly, mutations of Fgd4 (Frabin) are associated with the peripheral nerve disease, Charcot-Marie-Tooth disease (20,21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

Huber¹,

Mårtensson²,

Bokoch

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Members of the Fgd (faciogenital dysplasia) gene family encode a group of critical guanine nucleotide exchange factors (GEFs), which, by specifically activating Cdc42, control cytoskeleton-dependent membrane rearrangements. In its first characterization, we find that FGD2 is expressed in antigen-presenting cells, including B lymphocytes, macrophages, and dendritic cells. In the B lymphocyte lineage, FGD2 levels change with developmental stage. In both mature splenic B cells and immature bone marrow B cells, FGD2 expression is suppressed upon activation through the B cell antigen receptor. FGD2 has a complex intracellular localization, with concentrations found in membrane ruffles and early endosomes. Although endosomal localization of FGD2 is dependent on a conserved FYVE domain, its C-terminal pleckstrin homology domain mediates recruitment to membrane ruffles. FGD2 overexpression promotes the activation of Cdc42 and leads to elevated JNK1 activity in a Cdc42-but not Rac1-dependent fashion. These findings are consistent with a role of FGD2 in leukocyte signaling and vesicle trafficking in cells specialized to present antigen in the immune system.

show abstract

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

Huber¹,

Mårtensson²,

Bokoch

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…As a result, we found a novel Rho family GEF gene, KIAA0793. The KIAA0793 protein shows sequence similarity to a human faciogenital dysplasia gene product (FGD1), which is a specific activator of Cdc42 (36) and appears to be a family of related Cdc42-GEFs including mouse Fgd2 and Fgd3 (37) and mouse Frabin (38).…”

mentioning

confidence: 99%

Src Kinase Regulates the Activation of a Novel FGD-1-related Cdc42 Guanine Nucleotide Exchange Factor in the Signaling Pathway from the Endothelin A Receptor to JNK

Miyamoto

Yamauchi

Itoh

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Small GTPases act as binary switches by cycling between an inactive (GDP-bound) and an active (GTPbound) state. Upon stimulation with extracellular signals, guanine-nucleotide exchange factors (GEFs) stimulate the exchange of GDP to GTP to shift toward the active forms of small GTPases, recognizing the downstream targets. Here we show that KIAA0793, containing substantial sequence homology with the catalytic Dbl homology domain of the faciogenital dysplasia gene product (FGD1), is a specific GEF for Cdc42. We, therefore, tentatively named it FRG (FGD1-related Cdc42-GEF). Src kinase directly phosphorylates and activates FRG, as Vav family GEFs. Additionally, FRG is involved in the signaling pathway from the endothelin A receptor to c-Jun N-terminal kinase, resulting in the inhibition of cell motility. These results suggest that FRG is a member of Cdc42-GEF and plays an important role in the signaling pathway downstream of G proteincoupled receptors.

show abstract

“…4) However, it is important to characterize the full length GEFs; because most GEFs also contain regulatory domains that are responsible for turning on or turning off the DH-PH-moduledriven GEF activity. 4) FGD1 and FGD3 have highly homologous DH-PH modules, which can induce a large number of striking filopodia extensions in Swiss 3T3 fibroblasts, 21,22) indicating that both of them act as GEFs for Cdc42. However, when expressed as a full-length form, FGD1 induces long-finger like protrusions (i.e., filopodia) and FGD3 induces broad sheet-like protrusions (i.e., lamellipodia).…”

Section: Resultsmentioning

confidence: 99%

Role of FGD1, a Cdc42 Guanine Nucleotide Exchange Factor, in Epidermal Growth Factor-Stimulated c-Jun NH2-Terminal Kinase Activation and Cell Migration

Oshima

Fujino

Ando

et al. 2011

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Cell migration is an essential process involved in development, wound healing, tumor invasion, and metastasis. In migrating cells, re-organization of the actin cytoskeleton occurs dynamically to provide the force for cell motility. The Rho family small guanosine 5Ј-triphosphate (GTP)-binding proteins (G-proteins), consisting mainly of the Rho, Rac, and Cdc42 subfamilies, are key molecular switches that regulate various actin cytoskeleton-dependent cell functions, including cell shape change, cell migration, cell adhesion, and cytokinesis.1-3) Like all G-proteins, Rho family proteins act as binary switches by cycling between an inactive (guanosine 5Ј-diphosphate (GDP)-bound) and an active (GTP-bound) conformation state.Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate active forms of Rho proteins, whereas GTPase-activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho proteins to inactivate the switch. In theory, the active state of Rho proteins may be obtained through stimulation of a GEF or inhibition of a GAP, however, most evidence indicates that GEFs are the critical mediators for the activation of Rho proteins. 4)FGD1, a GEF for Cdc42, was originally identified and characterized by positional cloning in a family in which the phenotype of the developmental disorder (known as the faciogenital dysplasia or Aarskog-Scott syndrome; AAS) was associated with an X; 8 translocation.5,6) Further genetic analyses revealed that different types of point mutations occurred in FGD1 are also responsible for AAS.7) While most mutations were found in the DH domain or adjacent PH domain of FGD1, Orrico et al. reported that a patient with a missense mutation in the proline-rich domain of FGD1 showed typical clinical features as AAS.8) In this mutant FGD1, the serine residue at position 205 is replaced with isoleucine and the DH-PH modules necessary for the GEF activity remain intact.In our previous reports, we revealed that FGD1 and FGD3, a homologue of FGD1, underwent proteasomal degradation through the polyubiquitination by the ubiquitin ligase SCF FWD1 . 9,10) FGD1 and FGD3 share strikingly similar Dbl homology (DH) domains and adjacent pleckstrin homology (PH) domains, both of which (i.e., DH-PH modules) are responsible for guanine nucleotide exchange, however, there exist remarkable differences in their biological functions. 10)Whereas FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTPbound Cdc42 was significantly increased by the inducible expression of FGD3.10) Furthermore, FGD1 and FGD3 reciprocally regulated cell motility; when inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migrations whereas FGD3 inhibited it. 10)Although higher sequence similarity between FGD1 and FGD3 is observed in their DH-PH modules, there exist significant differences in their sequence in other regions; most prominently, FGD3 lacks the N-terminal proline-rich domain conserved in FGD1. Proline-rich sequences are k...

show abstract

Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue

Cited by 41 publications

References 28 publications

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

Src Kinase Regulates the Activation of a Novel FGD-1-related Cdc42 Guanine Nucleotide Exchange Factor in the Signaling Pathway from the Endothelin A Receptor to JNK

Role of FGD1, a Cdc42 Guanine Nucleotide Exchange Factor, in Epidermal Growth Factor-Stimulated c-Jun NH2-Terminal Kinase Activation and Cell Migration

Contact Info

Product

Resources

About