RhoG Signals in Parallel with Rac1 and Cdc42

Wennerberg, Krister; Ellerbroek, Shawn M.; Liu, Rong Yu; Karnoub, Antoine E.; Burridge, Keith; Der, Channing J.

doi:10.1074/jbc.m203816200

Cited by 96 publications

(100 citation statements)

References 55 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…pZIP-raf(Y340D) encodes an amino terminal-truncated and constitutively activated variant of human Raf-1 and has been characterized previously (Khosravi-Far et al, 1995). pGEX-GST-BCR-GAP encodes the catalytic domain of BCR which is a GAP for Rac1, Cdc42, and RhoA and has been characterized previously (Wennerberg et al, 2002). pcDNA3-myc-Tiam1 C1199 encodes an amino-terminally truncated, constitutively activated mutant of Tiam1 and was obtained from G Bollag (Onyx Pharmaceuticals, Richmond, VA, USA) and has been characterized previously (Lambert et al, 2002).…”

Section: Molecular Constructsmentioning

confidence: 99%

“…pCMV6M Pak1, pCDNA His3(T7) Pak5, pCMV6M Pak6 were obtained from Dr Jonathan Chernoff (Fox Chase Cancer Center). pRK5-myc-POSH-RBD encodes the isolated Rac1-GTP binding fragment from Posh, a Rac1-specific effector (Wennerberg et al, 2002). Reporter constructs where the luciferase gene is under the control of minimal promoters with NF-kB (Galang et al, 1996) or SRF responsive elements, or the human cyclin D1 promoter (Albanese et al, 1995) have been described previously.…”

Section: Molecular Constructsmentioning

confidence: 99%

“…These transcription factors then upregulate the expression of cell cycle regulatory proteins, such as cyclin D1, that promote G1-to S-phase progression. In addition, activated Rac1 has been shown to stimulate phosphatidylinositol-3 kinase (PI3K)-dependent activation of the AKT serine/threonine kinase (Keely et al, 1997;Coniglio et al, 2001;Rul et al, 2002;Wennerberg et al, 2002). This implicates Rac1 in antiapoptotic signaling and provides a mechanism by which aberrant Rac1 activity can promote cellular transformation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation

et al. 2004

View full text Add to dashboard Cite

A novel splice variant of Rac1, designated Rac1b, is expressed in human breast and colon carcinoma cells. Rac1b contains an additional 19 amino-acid insert immediately behind the switch II domain, a region important for Rac1 interaction with regulators and effectors. Recent studies showed that Rac1b exhibited the biochemical properties of a constitutively activated GTPase, yet it showed impaired interaction with downstream effectors, suggesting that Rac1b may be defective in biological activity. Whether Rac1b is a biologically active protein was not addressed. Therefore, we evaluated the biochemical, signaling and growth-promoting properties of authentic Rac1b. Similar to previous observations, we found that Rac1b showed enhanced intrinsic guanine nucleotide exchange activity, impaired intrinsic GTPase activity, and failed to interact with RhoGDI. Surprisingly, we found that Rac1b, like the constitutively-activated and transforming Rac1(Q61L) mutant, promoted growth transformation of NIH3T3 cells. Rac1b-expressing cells also showed a loss of density-dependent and anchorage-dependent growth. Surprisingly, unlike activated Rac1(61L), Rac1b did not show enhanced activation of the nuclear factor jB (NF-jB) transcription factor or stimulate cyclin D1 expression, the signaling activities that best correlate with Rac1 transforming activity. However, Rac1b did promote activation of the AKT serine/threonine kinase. Therefore, we suggest that Rac1b selectively activates a subset of Rac1 downstream signaling pathways to facilitate cellular transformation.

show abstract

Section: Molecular Constructsmentioning

confidence: 99%

Section: Molecular Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation

et al. 2004

View full text Add to dashboard Cite

show abstract

“…RhoG shares significant homology with Rac1 (72% identity) and is believed to function upstream of Rac1 and Cdc42 (Gauthier-Rouviere et al, 1998;Katoh et al, 2000Katoh et al, , 2006. However, other studies suggest that RhoG signals in parallel of Rac1 and Cdc42 rather than upstream (Wennerberg et al, 2002;Prieto-Sanchez and Bustelo, 2003). Although several regulators of the RhoA, Rac1 and Cdc42 GTPases have been characterized few regulators of RhoG have been identified.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

“…This raises the question of how thymocytes are affected when multiple types of GTPases are coordinately activated. Dbs is an exchange factor which activates RhoA and CDC42, with weaker activation of RhoG [25][26][27]. Its rat ortholog is known as Ost [28,29].…”

Section: Introductionmentioning

confidence: 99%

The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

2004

View full text Add to dashboard Cite

Specific members of the Rho family of GTPases exert unique influences on thymocyte proliferation, differentiation and deletion. Dbs is a guanine nucleotide exchange factor which is expressed throughout thymocyte development and is able to activate the Rho family GTPases CDC42, RhoA and RhoG. Transgenic mice expressing an activated form of Dbs had increased numbers of double-negative thymocytes. The Dbs transgene promoted expansion of double-negative thymocytes in the absence of pre-TCR, but had no effect on pre-TCR-dependent differentiation of double-negative thymocytes into double-positive thymocytes. Transgenic double-positive thymocytes were proliferative in vivo, but were also susceptible to apoptosis in vivo and in vitro. The transgenic single-positive thymocytes had attenuated proliferative responses following TCR ligation, and were depleted rather than expanded during culture in the presence of anti-CD3. When expressing a positively selectable TCR, transgenic double-positive thymocytes were increased in number and activated, but the output of single-positive thymocytes was reduced. Transgenic double-positive thymocytes were acutely sensitive to deletion by TCR ligation in vivo. These results indicate that activation of Dbs has the potential to promote proliferation throughout thymocyte development, but also sensitizes double-positive and single-positive thymocytes to deletion.

show abstract

RhoG Signals in Parallel with Rac1 and Cdc42

Cited by 96 publications

References 55 publications

Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation

Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation

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

The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

Contact Info

Product

Resources

About