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Regulation of c-myc expression by PDGF through Rho GTPases

Nature Cell Biology volume 3, pages 580–586 (2001)Cite this article

Abstract

Src family protein-tyrosine kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation and apoptosis. Surprisingly, these kinases also participate in mitogenic signalling by receptors that themselves exhibit an intrinsic protein-tyrosine kinase activity, inclu-ding those for platelet-derived growth factor (PDGF), epidermal growth factor and colony-stimulating factor-1. Indeed, Src kinases are strictly required for the nuclear expression of the c-myc proto-oncogene and thus for DNA synthesis in response to PDGF. However, the nature of the signalling pathways by which Src kinases participate in the induction of c-myc expression by tyrosine kinase receptors is still unknown. Here we show that PDGF enhances c-myc expression and stimulates the c-myc promoter in a Src-dependent manner, and that neither Ras nor the mitogen-activated protein kinase pathway mediate these effects. In contrast, we present evidence that PDGF stimulates Vav2 through Src, thereby initiating the activation of a Rac-dependent pathway that controls the expression of the c-myc proto-oncogene.

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Figure 1: PDGF stimulation of c-myc expression is dependent on the activity of Src-related kinases.
Figure 2: Stimulation of the myc promoter by the PDGF-receptor–Src pathway is independent of Ras–MAPK activation.
Figure 3: Rho GTPases participate in the Src-dependent activation of the c-myc promoter.
Figure 4: Role of Vav2 in the Src-dependent activation of the c-myc promoter by PDGF.
Figure 5

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Acknowledgements

We thank H. Varmus, P. Schwartzberg, K. Aktories, R. Pestell, A. Aronheim and X. R. Bustelo for providing us with the pSM-Src YF and pSM-Src YFKM, CAIO-Src 251, pGEX2T-GST–CNF-1, pMyc-Luc, pRSV Sos myristoylated and Vav2 cDNAs, respectively; J. I. Lee for the gift of the anti-Vav2 antisera; and R. Visconti and S. Pece for many helpful discussions. M.C. was on leave from the Dipartimento di Biologia e Patologia Cellulare e Molecolare 'L. Califano', Università degli Studi di Napoli 'Federico II', via S. Pansini 5, 80131, Naples, Italy.

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  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Mario Chiariello, Maria Julia Marinissen & J. Silvio Gutkind

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  1. Mario Chiariello
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Correspondence to J. Silvio Gutkind.

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Chiariello, M., Marinissen, M. & Gutkind, J. Regulation of c-myc expression by PDGF through Rho GTPases. Nat Cell Biol 3, 580–586 (2001). https://doi.org/10.1038/35078555

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