G&amp;alpha;13 Regulation of Proto-Dbl Signaling

Vanni, Cristina; Mancini, Patrizia; Ottaviano, Catherine; Ognibene, Marzia; Parodi, Alessia; Merello, Elisa; Russo, Chiara; Varesio, Luigi; Zheng, Yi; Torrisi, Maria Rosaria; Eva, Alessandra

doi:10.4161/cc.6.16.4574

Cited by 14 publications

(14 citation statements)

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“…7). In this regard, multiple Rho GEFs that have been proposed to link G 12/13 -coupled GPCRs to Rho activation, including PDZ-RhoGEF (PRG), leukemia-associated Rho GEF (LARG), p115-RhoGEF (p115), and lymphoid blast crisis (Lbc), its longer transcript fused to an AKAP (A kinase anchor protein), AKAP-Lbc (8,9), proto-Dbl (10,11), and Lfc (12). Among them, PRG, LARG, and p115 share the presence of a RGS homology domain, which is responsible for their interaction with G␣ 12 and its family member, G␣ 13 (6,8,13).…”

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confidence: 99%

PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation

Mikelis

Palmby

Simaan

et al. 2013

Journal of Biological Chemistry

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Background: Many Rho GEFs have been proposed to link GPCRs to Rho activation. Results: PDZ-RhoGEF and LARG double deficiency leads to embryonic lethality and, along with p115 RhoGEF, are required for thrombin-induced cell migration, proliferation, and RhoA activation. Conclusion: PDZ-RhoGEF, LARG, and p115 RhoGEF mediate G␣ 12/13 signaling to RhoA. Significance: These findings identify novel targets for pharmacological intervention in diseases involving aberrant GPCR signaling.

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confidence: 99%

PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation

Mikelis

Palmby

Simaan

et al. 2013

Journal of Biological Chemistry

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“…Activation of Rho, in response to LPA, is thought to involve stimulation of the ␣-subunit of the heterotrimeric G 12 /G 13 proteins that act on a family of highly related Rho-specific GEFs, including p115-RhoGEF, PDZ-Rho-GEF, and LARG (32)(33)(34). Moreover, we have shown that activated G␣ 13 induces activation of the GEF Dbl stimulating its association with ezrin (14). The two mechanisms by which Rho acts both upstream and downstream of ERM proteins are compatible with a system that creates a positive feedback loop which promotes activation of Rho by ERM association with hamartin and/or by inhibition of Rho GDI.…”

mentioning

confidence: 61%

“…NIH-3T3 cells were stably cotransfected with onco-Dbl together with shham or sh-ns. Cell lysates were obtained and processed as previously described (14). Immunoprecipitation was performed by incubating cell lysates with polyclonal anti-GST antibody (Molecular Probes) to detect GST-Dbl fusion proteins, monoclonal anti-ezrin antibody (Santa Cruz Biotechnology), polyclonal anti-hamartin antibody (Santa Cruz Biotechnology) for detection of endogenous and FL-ham, or with monoclonal antibody against Xpress epitope (Invitrogen), for detection of ⌬-ham.…”

Section: Methodsmentioning

confidence: 99%

“…COS7 cells were transiently cotransfected with onco-Dbl together with FL-ham, ⌬-ham, or the empty vector, as control. Analysis of Cdc42 and Rac activation was performed as previously described (14).…”

Section: Methodsmentioning

confidence: 99%

“…NIH-3T3 cells were stably transfected with oncoDbl alone or together with sh-ezrin or sh-ns. The levels of activated p38MAPK and JNK were assessed as previously described (14).…”

Section: Methodsmentioning

confidence: 99%

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The Tumor Suppressor Hamartin Enhances Dbl Protein Transforming Activity through Interaction with Ezrin

Ognibene

Vanni

Segalerba

et al. 2011

Journal of Biological Chemistry

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The Rho guanine nucleotide exchange factor (GEF) Dbl binds to the N-terminal region of ezrin, a member of the ERM (ezrin, radixin, moesin) proteins known to function as linkers between the plasma membrane and the actin cytoskeleton. Here we have characterized the interaction between ezrin and Dbl. We show that binding of Dbl with ezrin involves positively charged amino acids within the region of the pleckstrin homology (PH) domain comprised between ␤1 and ␤2 sheets. In addition, we show that Dbl forms a complex with the tuberous sclerosis-1 (TSC-1) gene product hamartin and with ezrin. We demonstrate that hamartin and ezrin are both required for activation of Dbl. In fact, the knock-down of ezrin and hamartin, as well as the expression of a mutant hamartin, unable to bind ezrin, inhibit Dbl transforming and exchange activity. These results suggest that Dbl is regulated by hamartin through association with ezrin.ERMs (ezrin, radixin, moesin) 2 are ubiquitously expressed proteins that serve as membrane-cytoskeleton linkers and control diverse actin-based cellular functions including cell adhesion, cell motility, and protein localization, and participate in signaling pathways (1). ERM proteins share a conserved structure containing two domains: the C-terminal domain, that binds to actin, and the N-terminal FERM domain, which binds to protein targets at the plasma membrane and with several signaling proteins (2-14). In the inactive conformation the C terminus binds to the N terminus, thus preventing both interaction with membrane targets and actin. Activation of ERM proteins causes the release of this intramolecular binding and subsequent association of ERMs with the cytoskeleton and membrane proteins.Two distinct signals have been proposed as effectors of ERM protein activation: the phosphorylation, by Rho-dependent kinase ROCK, of a conserved C-terminal threonine residue, localized in a consensus C-terminal region of ERM proteins (15)(16)(17)(18)(19)(20), and the binding of phosphatidylinositol-4,5-biphosphate (21-23), produced by the activity of phopshatidylinositol 4-phosphate 5-kinase (24, 25), which in turn is stimulated by activated ROCK (26). Thus Rho, upon activation by guanine nucleotide exchange factors, may act as an upstream activator of ERMs.On the other hand, in vitro and in vivo studies have indicated that ERM proteins can act as upstream regulators of Rho GTPases by binding to the Rho GDP dissociation inhibitor (RhoGDI). This association is thought to displace RhoGDI from Rho GTPases, allowing them to be activated by their specific guanine nucleotide exchange factors (2). In this regard, a functional dependence of Rho GEFs on ezrin has been shown (27) and the association of ERM proteins with Rho GEF Dbl has been demonstrated (28 -30). Moreover, association of ezrin with a novel GEF that activates the small GTPase RhoG has been reported (8). Therefore, ERM proteins may act as upstream activators of Rho GTPases not only through their association with Rho GDI but also through their interaction with R...

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RhoA-Mediated Potential Regulation of Blood–Tumor Barrier Permeability by Bradykinin

Xue

2010

J Mol Neurosci

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The purpose of this work is to investigate the potential for the small G protein RhoA to play a role in bradykinin (BK)-induced actin cytoskeleton rearrangement, tight junction (TJ) protein disassembly, and an increase in blood-tumor barrier (BTB) permeability in rat brain microvascular endothelial cells (RBMECs). Our study used primary RBMECs as an in vitro BTB model and a RhoA inhibitor (C(3) exoenzyme) to establish whether RhoA played a role in the process of TJ disassembly, stress fiber formation, and increasing BTB permeability by BK. Data from the HRP flux and TEER assays revealed that BTB permeability was increased by BK induction. C(3) exoenzyme could partially inhibit endothelial leakage and restored normal TEER values in RBMECs. An obvious shift in occludin distribution from insoluble to soluble fractions was observed as assessed by Western blot, which was prevented by C(3) exoenzyme. In addition, C(3) exoenzyme inhibited BK-induced relocation of occludin from cellular borders into the cytoplasm, as well as stress fiber formation in RBMECs. A time-dependent increase in RhoA activity by BK administration was observed, which was inhibited by C(3) exoenzyme. RhoA activation is important for BK-induced increase in BTB permeability and appears to involve the ability for RhoA to mediate occludin disassembly and stress fiber formation.

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Gα13 Regulation of Proto-Dbl Signaling

Cited by 14 publications

References 53 publications

PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation

PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation

The Tumor Suppressor Hamartin Enhances Dbl Protein Transforming Activity through Interaction with Ezrin

RhoA-Mediated Potential Regulation of Blood–Tumor Barrier Permeability by Bradykinin

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