RhoA GTPase and Serum Response Factor Control Selectively the Expression of MyoD without Affecting Myf5 in Mouse Myoblasts

Carnac, Gilles; Primig, Michael; Kitzmann, Magali; Chafey, Philippe; Tuil, David; Lamb, Ned; Fernandez, Anne

doi:10.1091/mbc.9.7.1891

Cited by 113 publications

(136 citation statements)

References 59 publications

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“…Here, we present the first evidence that the nuclear localization of Myf5 is negatively controlled by RhoG/Rac1 and Cdc42Hs, likely through the activation of the JNK pathway. In contrast to MyoD, the myogenic factor Myf5 is not regulated by the RhoA/SRF pathway in C2C12 cells (Carnac et al, 1998), in agreement with our own results with L6 cells. Furthermore, expression of the DN Rac1 and Cdc42Hs mutants does not affect Myf5 localization, suggesting that DN and active Rac1 and Cdc42Hs mutants inhibit myogenesis through distinct signaling pathways.…”

Section: Opposing Roles For Rhog/rac1/cdc42hs and Rhoa In Regulating supporting

confidence: 93%

“…We found that expression of activated RhoA potentiates early steps of myogenesis, because it increases the expression of myogenin, troponin T, and MHC. These data are in agreement with recent studies showing that RhoA but not Rac1/Cdc42 signaling is an integral part of the skeletal muscle differentiation pathway (Carnac et al, 1998;Wei et al, 1998). Nevertheless, expression of activated RhoG, Rac1, and Cdc42Hs fully inhibits myogenesis of rat L6 myoblasts, preventing the expression of myogenin, troponin T, and MHC.…”

Section: Opposing Roles For Rhog/rac1/cdc42hs and Rhoa In Regulating supporting

confidence: 93%

“…The role of Rho GTPases, and particularly the Rac/ Cdc42Hs subgroup, in skeletal muscle differentiation is not well understood. Recent reports have revealed that the RhoA/SRF signaling cassette controls MyoD expression and skeletal muscle differentiation without affecting Myf5 expression (Carnac et al, 1998;Takano et al, 1998;Wei et al, 1998). In contrast, constitutively activated Rac1 does not appear to affect MyoD activity (Ramocki et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Critical Activities of Rac1 and Cdc42Hs in Skeletal Myogenesis: Antagonistic Effects of JNK and p38 Pathways

Mériane

Roux

Primig

et al. 2000

MBoC

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104

153

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The Rho family of GTP-binding proteins plays a critical role in a variety of cellular processes, including cytoskeletal reorganization and activation of kinases such as p38 and C-jun N-terminal kinase (JNK) MAPKs. We report here that dominant negative forms of Rac1 and Cdc42Hs inhibit the expression of the muscle-specific genes myogenin, troponin T, and myosin heavy chain in L6 and C2 myoblasts. Such inhibition correlates with decreased p38 activity. Active RhoA, RhoG, Rac1, and Cdc42Hs also prevent myoblast-to-myotube transition but affect distinct stages: RhoG, Rac1, and Cdc42Hs inhibit the expression of all muscle-specific genes analyzed, whereas active RhoA potentiates their expression but prevents the myoblast fusion process. We further show by two different approaches that the inhibitory effects of active Rac1 and Cdc42Hs are independent of their morphogenic activities. Rather, myogenesis inhibition is mediated by the JNK pathway, which also leads to a cytoplasmic redistribution of Myf5. We propose that although Rho proteins are required for the commitment of myogenesis, they differentially influence this process, positively for RhoA and Rac1/Cdc42Hs through the activation of the SRF and p38 pathways, respectively, and negatively for Rac1/Cdc42Hs through the activation of the JNK pathway. INTRODUCTIONThe development of skeletal muscle is a multistep process in which pluripotent mesodermal cells give rise to myoblasts that subsequently withdraw from the cell cycle and differentiate into plurinucleated myotubes. The earliest known markers for the skeletal muscle lineage are the four myogenic basic helix-loop-helix (bHLH) factors MyoD, Myf5, myogenin, and MRF4 (Molkentin and Olson, 1996;Arnold and Winter, 1998). During differentiation, myogenic bHLH factors activate muscle-specific genes (such as myosin light and heavy chains, troponin T, etc.) and coordinate withdrawal from the cell cycle (Lassar et al., 1994). In culture, differentiation of myocytes is induced when cells are exposed to medium containing a low concentration of mitogens (differentiation medium). These myogenic bHLH factors are targets of growth factor-signaling pathways that either negatively or positively regulate myogenic differentiation. In vivo experiments in mice have shown that sonic hedgehog and Wnt proteins coming from the dorsal neural tube control Myf5 expression, whereas MyoD is controlled by factors from the dorsal ectoderm (Munsterberg et al., 1995;Cossu et al., 1996;Stern et al., 1997). In addition, negative regulation by proteins such as BMP4, released by the lateral mesoderm, or proteins of the TGF␤ and FGF families plays an important role in this process (Pourquie et al., 1996).The Rho family of Ras-like GTPases are clustered in two distinct subgroups: the Rac/Cdc42 subgroup, which includes Rac1, Rac2, and Rac3, RhoG, Cdc42Hs, TC10, chp, and RhoH, and the Rho subgroup, in which RhoA, -B and -C, RhoD, RhoL, and Rnd1, Rnd2, and Rnd3 are found. Specific substitutions based on Ras studies result in the expression of proteins tha...

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Section: Opposing Roles For Rhog/rac1/cdc42hs and Rhoa In Regulating supporting

confidence: 93%

Section: Opposing Roles For Rhog/rac1/cdc42hs and Rhoa In Regulating supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Critical Activities of Rac1 and Cdc42Hs in Skeletal Myogenesis: Antagonistic Effects of JNK and p38 Pathways

Mériane

Roux

Primig

et al. 2000

MBoC

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104

153

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“…4A). Assays using different mutants of RhoA confirmed our conclusion: p120-catenin interacted better with the RhoA Thr19Asn mutant, an inactive RhoA mutant (4,32), than with the RhoA Gln63Leu mutant, a RhoA mutant with impaired GTPase activity and, therefore, constitutively bound to GTP molecules (15) (Fig. 4B, lanes 3 and 4).…”

supporting

confidence: 77%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.E-cadherin function is controlled posttranslationally by a family of proteins, named catenins, that bind to its cytosolic tail. Two members of this family, p120-catenin and ␤-catenin, interact at different sites of the E-cadherin molecule and are engaged in distinct functions. Whereas ␤-catenin is required for recruiting the actin cytoskeleton, p120-catenin is necessary for the stabilization of E-cadherin at the cell membrane (3). As a consequence, E-cadherin is rapidly internalized and degraded in the absence of p120-catenin (7, 13). Consequently, p120-catenin ablation in vivo causes E-cadherin deficiency, leading to severe defects in adhesion, cell polarity, and epithelial morphogenesis (7).Besides this role in regulating E-cadherin stability, p120-catenin interacts with other proteins involved in the modulation of cell-to-cell contacts. For instance, p120-catenin associates with Fer and Fyn tyrosine kinases (16,27,36). These kinases specifically phosphorylate ␤-catenin in Tyr142 (27), a modification that promotes release of ␤-catenin from the adherens junctional complex and transport to the nucleus (2, 27). Moreover, p120-catenin can interact with the Yes tyrosine kinase (27) and with a number of phosphotyrosine (PTyr) phosphatases, such as PTP (39), DEP1 (12), and SHP-1 (14, 21). These multiple associations suggest a role for p120-catenin as a scaffold protein for enzymes regulating events such as the stability of the adherens junctional complex (29).p120-catenin modulates the activity of other cellular factors. Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).Several results indicate that p...

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“…RhoA is an integral part of the skeletal muscle differentiation pathway and plays an obligatory role during myogenic induction (Carnac et al, 1998;Wei et al, 1998;Meriane et al, 2000). In addition, the level of RhoA GTP is increased by a pathway that promotes the commitment to myogenesis (Charrasse et al, 2003).…”

Section: Rhoa Gtpase Activity Decreases At the Onset Of Myoblast Fusionmentioning

confidence: 99%

RhoA GTPase Regulates M-Cadherin Activity and Myoblast Fusion

Charrasse

Comunale

Grumbach

et al. 2006

MBoC

121

131

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The Rho family of GTP-binding proteins plays critical roles during myogenesis induction. To elucidate their role later during myogenesis, we have analyzed RhoA function during myoblast fusion into myotubes. We find that RhoA activity is rapidly and transiently increased when cells are shifted into differentiation medium and then is decreased until myoblast fusion. RhoA activity must be down-regulated to allow fusion, because expression of a constitutively active form of RhoA (RhoAV14) inhibits this process. RhoAV14 perturbs the expression and localization of M-cadherin, a member of the Ca 2؉ -dependent cell-cell adhesion molecule family that has an essential role in skeletal muscle cell differentiation. This mutant does not affect N-cadherin and other proteins involved in myoblast fusion, ␤1-integrin and ADAM12. Active RhoA induces the entry of M-cadherin into a degradative pathway and thus decreases its stability in correlation with the monoubiquitination of M-cadherin. Moreover, p120 catenin association with M-cadherin is decreased in RhoAV14-expressing cells, which is partially reverted by the inhibition of the RhoA effector Rho-associated kinase ROCK. ROCK inhibition also restores M-cadherin accumulation at the cell-cell contact sites. We propose that the sustained activation of the RhoA pathway inhibits myoblast fusion through the regulation of p120 activity, which controls cadherin internalization and degradation.

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RhoA GTPase and Serum Response Factor Control Selectively the Expression of MyoD without Affecting Myf5 in Mouse Myoblasts

Cited by 113 publications

References 59 publications

Critical Activities of Rac1 and Cdc42Hs in Skeletal Myogenesis: Antagonistic Effects of JNK and p38 Pathways

Critical Activities of Rac1 and Cdc42Hs in Skeletal Myogenesis: Antagonistic Effects of JNK and p38 Pathways

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

RhoA GTPase Regulates M-Cadherin Activity and Myoblast Fusion

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