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  • Original Paper
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Ras protein is involved in the physiological regulation of phospholipase D by platelet derived growth factor

Oncogene volume 19, pages 431–437 (2000)Cite this article

Abstract

Lipid-derived metabolites play an important role in the regulation of cell responses to external stimuli, including cell growth control, transformation and apoptosis. Phospholipase D (PLD) is one of the critical elements in the regulation of lipid metabolism and the generation of second messengers, some of them involved in cell growth control. Oncogenic Ras proteins affect the activity of PLD by two alternate mechanisms, involving a positive activation and a feedback negative loop. Here we investigate the involvement of the proto-oncogenic Ras protein in the physiological activation of PLD induced by platelet-derived growth factor (PDGF). Over-expression of the wild type Ras protein or some of its regulatory components, such as Shc or Grb2, induces an amplification of PLD activation by PDGF challenge. Furthermore, blocking the endogenous Ras by expression of the dominant negative mutant, H-Ras-Asn17 completely eliminated the activation of PLD by PDGF. Thus, PDGF requires a complex system for PLD regulation implying the existence of at least two positive regulatory pathways, a Ras-dependent and a PKC-dependent mechanism. These results imply that PLD is an important element in signaling by Ras proteins that is altered after ras-induced transformation.

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Acknowledgements

We thank Leandro Fernández for the glucocorticoid receptors determination in Rat-2 cells, and Sonia del Rincón for helping us with the manuscript. Cells expressing Shc (clone R2S7) were generously provided by T Pawson. The plasmid pMMTV- Ras-N17 was a gift from L Feig, and the Grb2 gene a gift from D Bar-Sagi. This work was supported by Grant SAF98-0112-C02-01 from CICYT, Grant PB94-0009 from DGICYT, and Grants 08.1/0024/1997 and 08.1/0045.1/98 from Consejería de Educación of Comunidad de Madrid. Luisa Lucas is a Fellow from CICYT, Pilar Rodríguez is a fellow from Asociación Vasca del Cáncer and Fundación para la Investigación de Nuevas Estrategias Terapéuticas Oncológicas.

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  1. Luis del Peso

    Present address: University of Michigan, USA

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  1. Instituto de Investigaciones Biomédicas, CSIC, Arturo Duperier 4, Madrid, 28029, Spain

    Luisa Lucas, Luis del Peso, Pilar Rodríguez, Verónica Penalva & Juan Carlos Lacal

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Lucas, L., del Peso, L., Rodríguez, P. et al. Ras protein is involved in the physiological regulation of phospholipase D by platelet derived growth factor. Oncogene 19, 431–437 (2000). https://doi.org/10.1038/sj.onc.1203323

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