Positive regulation of skeletal myogenesis by R-Ras

Suzuki, Jotaro; Kaziro, Yoshito; Koide, Hiroshi

doi:10.1038/sj.onc.1203402

Cited by 21 publications

(13 citation statements)

References 50 publications

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“…R-Ras is known to induce haptotaxis in breast epithelia and skeletal myoblasts (Keely et al, 1999;Holly et al, 2000;Suzuki et al, 2000). We extend this observation further by showing that Q87L R-Ras potentiates chemokinesis or random cell movement driven by the presence of serum.…”

Section: Regulation Of Cell Migration By R-rassupporting

confidence: 60%

“…These authors also showed that R-Ras increased the affinity of the prototype platelet integrin, ␣IIb␤3, for soluble ligand, suggesting that R-Ras regulates integrins through an "inside-out" signaling mechanism. R-Ras has also been implicated in cell spreading (Berrier et al, 2000), cell survival (Suzuki et al, 1997;Osada et al, 1999) and haptotactic migration (Keely et al, 1999;Suzuki et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration

Holly

Larson

Parise

2005

MBoC

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The Ras family GTPase, R-Ras, elicits important integrin-dependent cellular behaviors such as adhesion, spreading and migration. While oncogenic Ras GTPases and R-Ras share extensive sequence homology, R-Ras induces a distinct set of cellular behaviors. To explore the structural basis for these differences, we asked whether the unique N-terminal 26 amino acid extension of R-Ras was responsible for R-Ras-specific signaling events. Using a 32D mouse myeloid cell line, we show that full-length R-Ras activates Rac and induces Rac-dependent cell spreading. In contrast, truncated R-Ras lacking its first 26 amino acids fails to activate Rac, resulting in reduced cell spreading. Truncated R-Ras also stimulates more ␤3 integrin-dependent cell migration than full-length R-Ras, suggesting that the N-terminus may negatively regulate cell movement. However, neither the subcellular localization of R-Ras nor its effects on cell adhesion are affected by the presence or absence of the N-terminus. These results indicate that the N-terminus of R-Ras positively regulates specific R-Ras functions such as Rac activation and cell spreading but negatively regulates R-Ras-mediated cell migration.

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Section: Regulation Of Cell Migration By R-rassupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration

Holly

Larson

Parise

2005

MBoC

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“…Other groups described opposite results, since treatment with PD restored di erentiation of infected Raf embryonic chick myoblasts (Dorman and Johnson, 1999). Moreover, other Ras isoforms, such as R-Ras, resulted in positive regulation of skeletal myogenesis (Suzuki et al, 2000).…”

Section: Introductionmentioning

confidence: 92%

Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

et al. 2002

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v-H-ras transformed C2C12 (C2Ras) myoblasts, overexpressing p21-Ras protein in the Ras-GTP active form, showed a di erentiation-defective phenotype when cultured in low serum as compared with C2C12 myoblasts. Accordingly, the purpose of the present study was to delineate the signaling pathways that restore C2Ras myoblasts di erentiation. Inhibition of p42/p44-MAPK with the chemical inhibitor PD98059, and activation of AKT/P70S6K and p38-MAPK with insulin, produced growth arrest (precluding the expression of PCNA, cyclin-D1 and retinoblastoma at the hyperphosphorylated state and inducing the expression of the cell cycle inhibitor p21 Cip ) and myogenesis (multinucleated myotubes formation and induction of creatine kinase, caveolin-3 and a-actin). Both events were accompanied by down-regulation of AP-1 and up-regulation of NF-kB transcriptional activities. Furthermore, inhibition of NFkB transcriptional activity by the use of the proteasome inhibitor MG132 totally precluded di erentiation by insulin+PD98059, demonstrating a direct role for NFkB on C2Ras myogenesis. C2Ras myoblasts failed to restore di erentiation when rapamycin or PD169316 were added in the presence of insulin+PD98059, indicating that the activation of both P70S6K and p38-MAPK was necessary to reach a fully di erentiated phenotype. Finally, transient transfection of a constitutively active Myr-EGFP-AKT-HA construct (in the presence of PD98059) restored C2Ras myogenesis by its ability to activate P70S6K and p38-MAPK. A crosstalk between P70S6K and p38-MAPK was observed under rapamycin treatment in both insulin or active AKT induced myogenesis. Our results are delineating an AKT/ P70S6K/p38-MAPK pathway involved in skeletal muscle di erentiation.

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“…Activated versions of R-Ras3 transform NIH 3T3 fibroblasts and induce neurite outgrowth in PC12 cells (16,31,32). R-Ras can transform some, but not other, cell types (12,39,61) and also has functions clearly different from those of Ras (62,70,78). Rap1 proteins, although originally proposed to act by antagonizing Ras function, have functions that are different from those of Ras, some of which may involve the regulation of integrin-mediated adhesion (6).…”

mentioning

confidence: 99%

Signaling Specificity by Ras Family GTPases Is Determined by the Full Spectrum of Effectors They Regulate

Rodríguez‐Viciana

Sabatier

McCormick

2004

Molecular and Cellular Biology

294

268

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Ras family GTPases (RFGs) regulate signaling pathways that control multiple biological processes. How signaling specificity among the closely related family members is achieved is poorly understood. We have taken a proteomics approach to signaling by RFGs, and we have analyzed interactions of a panel of RFGs with a comprehensive group of known and potential effectors. We have found remarkable differences in the ability of RFGs to regulate the various isoforms of known effector families. We have also identified several proteins as novel effectors of RFGs with differential binding specificities to the various RFGs. We propose that specificity among RFGs is achieved by the differential regulation of combinations of effector families as well as by the selective regulation of different isoforms within an effector family. An understanding of this new level of complexity in the signaling pathways regulated by RFGs is necessary to understand how they carry out their many cellular functions. It will also likely have critical implications in the treatment of human diseases such as cancer.

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Positive regulation of skeletal myogenesis by R-Ras

Cited by 21 publications

References 50 publications

The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration

The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration

Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

Signaling Specificity by Ras Family GTPases Is Determined by the Full Spectrum of Effectors They Regulate

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