Dbl family proteins

Whitehead, Ian P.; Campbell, Sharon L.; Rossman, Kent L.; Der, Channing J.

doi:10.1016/s0304-419x(96)00040-6

Cited by 250 publications

(393 citation statements)

References 103 publications

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“…As shown in Figure 3B, wild-type PLEKHG6 activated RhoG to the same extent as the exchange factor Trio-GEFD1, which was used as positive control. PLEKHG6-N351A containing a single amino acid substitution of the highly conserved Asn 351 in the DH domain had no exchange activity and therefore represents a catalytically dead form of PLEKHG6 (Whitehead et al, 1997;Aghazadeh et al, 1998;Debreceni et al, 2004). PLEKHG6 lacking the ezrin binding site (PLEKHG6-⌬CT) exhibited an exchange activity toward RhoG, similar to that of the full-length protein ( Figure 3B, left panel).…”

Section: Plekhg6 Displays Guanine Nucleotide Exchange Activity Prefermentioning

confidence: 87%

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

D'Angelo

Aresta

Blangy

et al. 2007

MBoC

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The mechanisms underlying functional interactions between ERM (ezrin, radixin, moesin) proteins and Rho GTPases are not well understood. Here we characterized the interaction between ezrin and a novel Rho guanine nucleotide exchange factor, PLEKHG6. We show that ezrin recruits PLEKHG6 to the apical pole of epithelial cells where PLEKHG6 induces the formation of microvilli and membrane ruffles. These morphological changes are inhibited by dominant negative forms of RhoG. Indeed, we found that PLEKHG6 activates RhoG and to a much lesser extent Rac1. In addition we show that ezrin forms a complex with PLEKHG6 and RhoG. Furthermore, we detected a ternary complex between ezrin, PLEKHG6, and the RhoG effector ELMO. We demonstrate that PLEKHG6 and ezrin are both required in macropinocytosis. After down-regulation of either PLEKHG6 or ezrin expression, we observed an inhibition of dextran uptake in EGF-stimulated A431 cells. Altogether, our data indicate that ezrin allows the local activation of RhoG at the apical pole of epithelial cells by recruiting upstream and downstream regulators of RhoG and that both PLEKHG6 and ezrin are required for efficient macropinocytosis. INTRODUCTIONThe membrane-cytoskeleton linker ezrin is mainly expressed in epithelial cells where it associates to the apical actin-rich structures such as microvilli (Berryman et al., 1993(Berryman et al., , 1995. Recent genetic analyses revealed that ezrin is essential for the morphogenesis of epithelial cells (Fiévet et al., 2007). In ezrin Ϫ/Ϫ mice, morphological defects in the apical domain of intestinal and retinal pigment epithelial cells have been observed (Saotome et al., 2004;Bonilha et al., 2006). In parietal cells, ezrin knockdown impairs the formation of canalicular apical membrane, resulting in severe achlorhydria (Tamura et al., 2005).How ezrin participates in the assembly of the apical actinrich structures such as microvilli is still poorly understood. The association of ezrin and the highly related proteins radixin and moesin with the cortical actin cytoskeleton is strictly regulated. ERM (ezrin, radixin, moesin) proteins contain a conserved globular N-terminal domain, called the FERM domain (Four point one ezrin, radixin, moesin), involved in the binding to both phosphatidylinositol 4,5 bisphosphate (PIP 2 ; Barret et al., 2000) and plasma membrane proteins and a C-terminal F-actin-binding domain that resides in the last 34 amino acids (Turunen et al., 1994;Bretscher et al., 2002). In the cytoplasm, ERM proteins exist in a closed conformation because of an intramolecular interaction between the N-terminal domain and the last 100 amino acids called N-and C-ERMAD (ERM association domain), respectively . This intramolecular association masks the binding sites for plasma membrane proteins and F-actin. An activation step is required to disrupt this association that occurs through conformational changes induced by sequential binding to PIP 2 and phosphorylation of a conserved C-terminal threonine residue (T567 in ezrin; Matsui et al., 1998;Fié...

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Section: Plekhg6 Displays Guanine Nucleotide Exchange Activity Prefermentioning

confidence: 87%

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

D'Angelo

Aresta

Blangy

et al. 2007

MBoC

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“…Detailed examination of the pathway linking GPCRs to JNK provided evidence that free bg dimers and, in some cellular systems, Ga 12 (Prasad et al, 1995) convey signals from this class of receptors to JNK. Furthermore, we and others have recently shown that JNK is potently activated by several naturally occurring human oncogenes (Coso et al, 1995b;Crespo et al, 1997;Minden et al, 1995;Whitehead et al, 1997). However, whereas a function for JNK in apoptosis has been recently established (Goillot et al, 1997;Johnson et al, 1996;Xia et al, 1995), the role for JNK in cellular transformation is still unclear.…”

Section: Novel Signaling Pathways Communicate Gpcrs To the Nucleusmentioning

confidence: 96%

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

1998

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“…Additionally, there remains a missing link between Src activation and the cytoskeletal remodeling that leads to podosome formation. Arhgef5 is a member of the Dbl family of GEFs (Whitehead et al, 1997). It has a Dbl homology (DH) domain that has GEF activity, a pleckstrin homology (PH) domain that binds to phosphoinositides, and a SH3 domain in its C-terminal region (Fig.…”

Section: Arhgef5 Is Identified As a Src Sh3 Domain-binding Proteinmentioning

confidence: 99%

The guanine nucleotide exchange factor Arhgef5 plays crucial roles in Src-induced podosome formation

Kuroiwa

Oneyama

Nada

et al. 2011

Journal of Cell Science

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SummaryPodosomes and invadopodia are actin-rich membrane protrusions that play a crucial role in cell adhesion and migration, and extracellular matrix remodeling in normal and cancer cells. The formation of podosomes and invadopodia is promoted by upregulation of some oncogenic molecules and is closely related to the invasive potential of cancer cells. However, the molecular mechanisms underlying the podosome and invadopodium formation still remain unclear. Here, we show that a guanine nucleotide exchange factor (GEF) for Rho family GTPases (Arhgef5) is crucial for Src-induced podosome formation. Using an inducible system for Src activation, we found that Src-induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3-binding protein. RNA interference (RNAi)-mediated depletion of Arhgef5 caused robust inhibition of Src-dependent podosome formation. Overexpression of Arhgef5 promoted actin stress fiber remodeling through activating RhoA, and the activation of RhoA or Cdc42 was required for Src-induced podosome formation. Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity. Furthermore, the pleckstrin homology (PH) domain of Arhgef5 was required for podosome formation, and Arhgef5 formed a ternary complex with Src and phosphoinositide 3-kinase when Src and/or Arhgef5 were upregulated. These findings provide novel insights into the molecular mechanisms of podosome and invadopodium formation induced by Src upregulation.

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Dbl family proteins

Cited by 250 publications

References 103 publications

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

Interaction of Ezrin with the Novel Guanine Nucleotide Exchange Factor PLEKHG6 Promotes RhoG-dependent Apical Cytoskeleton Rearrangements in Epithelial Cells

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

The guanine nucleotide exchange factor Arhgef5 plays crucial roles in Src-induced podosome formation

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