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Vol. 11, Issue 9, 2863-2872, September 2000

Death Effector Domain Protein PEA-15 Potentiates Ras Activation of Extracellular Signal Receptor-activated Kinase by an Adhesion-independent Mechanism

Joe W. Ramos,^* Paul E. Hughes,^* Mark W. Renshaw,^* Martin A. Schwartz,^* Etienne Formstecher, Hervé Chneiweiss, and Mark H. Ginsberg^*

 ^*Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037; and  Institut National de la Santé et de la Recherche Medicalé U114-Chaire de Neuropharmacologie, Collège de France, Paris, France

PEA-15 is a small, death effector-domain (DED)-containing protein that was recently demonstrated to inhibit tumor necrosis factor--induced apoptosis and to reverse the inhibition of integrin activation due to H-Ras. This led us to investigate the involvement of PEA-15 in Ras signaling. Surprisingly, PEA-15 activates the extracellular signal receptor-activated kinase (ERK) mitogen-activated protein kinase pathway in a Ras-dependent manner. PEA-15 expression in Chinese hamster ovary cells resulted in an increased mitogen-activated protein kinase kinase and ERK activity. Furthermore, PEA-15 expression leads to an increase in Ras guanosine 5'-triphosphate loading. PEA-15 bypasses the anchorage dependence of ERK activation. Finally, the effects of PEA-15 on integrin signaling are separate from those on ERK activation. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to activate ERK. The ability of PEA-15 to simultaneously inhibit apoptosis and potentiate Ras-to-Erk signaling may be of importance for oncogenic processes.

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Corresponding author. E-mail address: ramos{at}biology.rutgers.edu.

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Molecular Biology of the Cell
Vol. 11, 2863-2872, September 2000
Copyright © 2000 by The American Society for Cell Biology

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