Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases

Olson, Michael F.; Pasteris, N. German; Gorski, Jerome L.; Hall, Alan

doi:10.1016/s0960-9822(02)70786-0

Cited by 201 publications

(206 citation statements)

References 33 publications

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“…This began with the localization of both FGD1 and Cdc42 at the Golgi membranes (Erickson et al, 1996;Estrada et al, 2001), and we have shown here that a loss of the activities of either FGD1 or Cdc42 results in similar aberrant transport phenotypes. Furthermore, FGD1 inhibitors affect both Cdc42 activity (Olson et al, 1996) and Cdc42 binding to the Golgi complex (see Figure 6). Given that Cdc42 can be activated by many different GEFs (Hoffman and Cerione, 2002), why are none of these able to efficiently substitute for FGD1 in the support of post-Golgi transport?…”

Section: Discussionmentioning

confidence: 99%

“…For the latter, the GFP-FGD1-AS mutant comprises nearly full-length Fgd1 cDNA that encodes a naturally occurring FGDY-related alternative FGD1 transcript that lacks 36 amino acids in exon 6. This alters the FGD1 DH domain and generates a dominant-negative FGD1 protein that cannot activate Cdc42 (Olson et al, 1996). In contrast, the GFP-FGD1-dbdel fusion construct contains deletions of residues 146-188 and thus removes N-terminal inhibition and results in a constitutively active form of FGD1.…”

Section: Fgd1 Deficit Inhibits Constitutive Post-golgi Transportmentioning

confidence: 99%

“…Given that FGD1 has specific GEF activity toward Cdc42 (Olson et al, 1996), we reasoned that Cdc42 activation might be inhibited in FGDY, where the GEF activity of FGD1 is missing. Activation of Cdc42, in turn, is known to be required for the delivery of many proteins to the cell surface (Kroschewski et al, 1999;Musch et al, 2001).…”

Section: Expression Of Gdp-bound Cdc42 Mimics Fgd1 Deficitmentioning

confidence: 99%

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Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Egorov

Capestrano

Vorontsova

et al. 2009

MBoC

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Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). FGD1 encodes a guanine nucleotide exchange factor that specifically activates the GTPase Cdc42. In turn, Cdc42 is an important regulator of membrane trafficking, although little is known about FGD1 involvement in this process. During development, FGD1 is highly expressed during bone growth and mineralization, and therefore a lack of the functional protein leads to a severe phenotype. Whether the secretion of proteins, which is a process essential for bone formation, is altered by mutations in FGD1 is of great interest. We initially show here that FGD1 is preferentially associated with the trans-Golgi network (TGN), suggesting its involvement in export of proteins from the Golgi. Indeed, expression of a dominant-negative FGD1 mutant and RNA interference of FGD1 both resulted in a reduction in post-Golgi transport of various cargoes (including bone-specific proteins in osteoblasts). Live-cell imaging reveals that formation of post-Golgi transport intermediates directed to the cell surface is inhibited in FGD1-deficient cells, apparently due to an impairment of TGN membrane extension along microtubules. These effects depend on FGD1 regulation of Cdc42 activation and its association with the Golgi membranes, and they may contribute to FGDY pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Fgd1 Deficit Inhibits Constitutive Post-golgi Transportmentioning

confidence: 99%

Section: Expression Of Gdp-bound Cdc42 Mimics Fgd1 Deficitmentioning

confidence: 99%

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Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Egorov

Capestrano

Vorontsova

et al. 2009

MBoC

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“…As we identified a functional role of ERM proteins in the local recruitment and activation of Cdc42, we were interested to test the role of ERM proteins in modulating GEF activity and behavior. We analyzed the morphological changes in MDA-MB-231 cells after overexpression of a panel of GEFs: the Cdc42-specific Rho GEF FGD1 and the Cdc42/Rho-specific GEF onco-Dbl (Olson et al, 1996); the Rac-specific GEF Tiam1 (constitutively activated by an N-terminal deletion; Michiels et al, 1997); and the Rho-specific GEF p190RhoGEF (van Horck et al, 2001). Expression of FGD1 in MDA-MB-231 cells induces formation of filopodia and membrane ruffles ( Figure 6A, top panel left).…”

Section: N-ermad(e244k) Disrupts the Morphological Reorganization Indmentioning

confidence: 99%

Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

Prag

Parsons

Keppler

et al. 2007

MBoC

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Establishment of polarized cell morphology is a critical factor for migration and requires precise spatial and temporal activation of the Rho GTPases. Here, we describe a novel role of the actin-binding ezrin/radixin/moesin (ERM)-protein ezrin to be involved in recruiting Cdc42, but not Rac1, to lipid raft microdomains, as well as the subsequent activation of this Rho GTPase and the downstream effector p21-activated kinase (PAK)1, as shown by fluorescence lifetime imaging microscopy. The establishment of a leading plasma membrane and the polarized morphology necessary for random migration are also dependent on ERM function and Cdc42 in motile breast carcinoma cells. Mechanistically, we show that the recruitment of the ERM-interacting Rho/Cdc42-specific guanine nucleotide exchange factor Dbl to the plasma membrane and to lipid raft microdomains requires the phosphorylated, active conformer of ezrin, which serves to tether the plasma membrane or its subdomains to the cytoskeleton. Together these data suggest a mechanism whereby precise spatial guanine nucleotide exchange of Cdc42 by Dbl is dependent on functional ERM proteins and is important for directional cell migration.

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“…14, April 2003 1627 Gavin et al, 2001). Because many DH domains show exchange activity on multiple Rho GTPase family members (Hart et al, 1994;Olson et al, 1996), we tested DH domain specificity using recombinant GST fusion proteins in several complementary assays. Figure 2A displays the intersectin 1L domain structure and aa position of the recombinant fusion proteins used in this study.…”

Section: Intersectin 1l Gef Inhibitory Mechanismmentioning

confidence: 99%

Intersectin 1L Guanine Nucleotide Exchange Activity Is Regulated by Adjacent src Homology 3 Domains That Are Also Involved in Endocytosis

Zamanian

Kelly

2003

MBoC

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Intersectin 1L is a scaffolding protein involved in endocytosis that also has guanine nucleotide exchange activity for Cdc42. In the context of the full-length protein, the catalytic exchange activity of the DH domain is repressed. Here we use biochemical methods to dissect the mechanism for this inhibition. We demonstrate that the intersectin 1L SH3 domains, which bind endocytic proteins, directly inhibit the activity of the DH domain in assays for both binding and exchange of Cdc42. This inhibitory mechanism seems to act through steric hindrance of Cdc42 binding by an intramolecular interaction between the intersectin 1L SH3 domain region and the adjacent DH domain. Surprisingly, the mode of SH3 domain binding is other than through the proline peptide binding pocket. The dual role of the SH3 domains in endocytosis and repression of exchange activity suggests that the intersectin 1L exchange activity is regulated by endocytosis. We show that the endocytic protein, dynamin, competes for binding to the SH3 domains with the neural Wiskott-Aldrich Syndrome protein, an actin filament nucleation protein that is a substrate for activated Cdc42. Swapping of SH3 domain binding partners might act as a switch controlling the actin nucleation activity of intersectin 1L. INTRODUCTIONRho family guanine nucleotide exchange factors (GEFs) are critical regulatory proteins of cellular pathways that require regulation of actin cytoskeleton rearrangements (for review see Zheng, 2001;Hoffman and Cerione, 2002). Their conserved catalytic domain, the Dbl homology (DH) domain (Hart et al., 1991(Hart et al., , 1994 catalyzes the release of GDP from Rho GTPases and thus subsequent activation by GTP binding. DH domains are invariably found upstream and adjacent to pleckstrin homology (PH) domains, which are thought to influence their activity (Liu et al., 1998;Das et al., 2000) and membrane localization (Whitehead et al., 1999). The noncatalytic parts of the structurally complex GEFs link the exchange activity to cellular processes and inhibit the DH domain exchange activity (Zheng, 2001;Hoffman and Cerione, 2002). Cellular inputs, such as protein (Hart et al., 1998;Scita et al., 1999;Innocenti et al., 2002) and phospholipid binding to (Han et al., 1998;Nimnual et al., 1998;Crompton et al., 2000;Das et al., 2000;Russo et al., 2001), and phosphorylation of (Crespo et al., 1997;Han et al., 1997;Schuebel et al., 1998;Aghazadeh et al., 2000) these regulatory regions derepress exchange activity. Integration of cellular signals by Rho GEFs can focus GTPase activity to allow temporal and spatially localized activation of actin cytoskeletal rearrangements.Intersectin 1L, a neuronal splice variant of the endocytic scaffolding protein intersectin 1, is a Rho family GEF that is composed of two N-terminal EH domains (EH1, EH2), a large region of putative coiled-coils, five SH3 domains (SH3A, B, C, D, and E; Roos and Kelly, 1998;Yamabhai et al., 1998;Okamoto et al., 1999;Sengar et al., 1999), followed by the DH and PH domains and a carboxyl-terminal ...

show abstract

Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases

Abstract: We conclude that FGD1 and Vav are regulators of the Rho GTPase family. Along with their target proteins Cdc42, Rac and Rho, FGD1 and Vav control essential signals required during embryonic development.

Cited by 201 publications

References 33 publications

Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

Intersectin 1L Guanine Nucleotide Exchange Activity Is Regulated by Adjacent src Homology 3 Domains That Are Also Involved in Endocytosis

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