Mol. Biol. Cell 11 (9): 2863-2872

Copyright © 2000 by The American Society for Cell Biology.

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.

---

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

---

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

PEA-15 Induces Autophagy in Human Ovarian Cancer Cells and Is Associated with Prolonged Overall Survival.

C. Bartholomeusz, D. Rosen, C. Wei, A. Kazansky, F. Yamasaki, T. Takahashi, H. Itamochi, S. Kondo, J. Liu, and N. T. Ueno (2008)
Cancer Res. 68, 9302-9310
 |  Abstract »  |  Full Text »  |  PDF »

Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma.

A. H. Stegh, S. Kesari, J. E. Mahoney, H. T. Jenq, K. L. Forloney, A. Protopopov, D. N. Louis, L. Chin, and R. A. DePinho (2008)
PNAS 105, 10703-10708
 |  Abstract »  |  Full Text »  |  PDF »

ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15.

H. Vaidyanathan, J. Opoku-Ansah, S. Pastorino, H. Renganathan, M. L. Matter, and J. W. Ramos (2007)
PNAS 104, 19837-19842
 |  Abstract »  |  Full Text »  |  PDF »

Mutations in ERK2 Binding Sites Affect Nuclear Entry.

M. N. Yazicioglu, D. L. Goad, A. Ranganathan, A. W. Whitehurst, E. J. Goldsmith, and M. H. Cobb (2007)
J. Biol. Chem. 282, 28759-28767
 |  Abstract »  |  Full Text »  |  PDF »

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15.

M. Gervais, C. Dugourd, L. Muller, C. Ardidie, B. Canton, L. Loviconi, P. Corvol, H. Chneiweiss, and C. Monnot (2006)
Mol. Biol. Cell 17, 3940-3951
 |  Abstract »  |  Full Text »  |  PDF »

Cyclic AMP Selectively Uncouples Mitogen-Activated Protein Kinase Cascades from Activating Signals.

G. W. Pearson, S. Earnest, and M. H. Cobb (2006)
Mol. Cell. Biol. 26, 3039-3047
 |  Abstract »  |  Full Text »  |  PDF »

Proteomic-Based Prognosis of Brain Tumor Patients Using Direct-Tissue Matrix-Assisted Laser Desorption Ionization Mass Spectrometry.

S. A. Schwartz, R. J. Weil, R. C. Thompson, Y. Shyr, J. H. Moore, S. A. Toms, M. D. Johnson, and R. M. Caprioli (2005)
Cancer Res. 65, 7674-7681
 |  Abstract »  |  Full Text »  |  PDF »

Phosphorylation of Phosphoprotein Enriched in Astrocytes (PEA-15) Regulates Extracellular Signal-regulated Kinase-dependent Transcription and Cell Proliferation.

J. Krueger, F.-L. Chou, A. Glading, E. Schaefer, and M. H. Ginsberg (2005)
Mol. Biol. Cell 16, 3552-3561
 |  Abstract »  |  Full Text »  |  PDF »

Calcium/Calmodulin-dependent Protein Kinase II Regulation of c-FLIP Expression and Phosphorylation in Modulation of Fas-mediated Signaling in Malignant Glioma Cells.

B. F. Yang, C. Xiao, W. H. Roa, P. H. Krammer, and C. Hao (2003)
J. Biol. Chem. 278, 7043-7050
 |  Abstract »  |  Full Text »  |  PDF »

Multiple Members of the Mitogen-activated Protein Kinase Family Are Necessary for PED/PEA-15 Anti-apoptotic Function.

G. Condorelli, A. Trencia, G. Vigliotta, A. Perfetti, U. Goglia, A. Cassese, A. M. Musti, C. Miele, S. Santopietro, P. Formisano, et al. (2002)
J. Biol. Chem. 277, 11013-11018
 |  Abstract »  |  Full Text »  |  PDF »

Identification and Characterization of DEDD2, a Death Effector Domain-containing Protein.

W. Roth, F. Stenner-Liewen, K. Pawlowski, A. Godzik, and J. C. Reed (2002)
J. Biol. Chem. 277, 7501-7508
 |  Abstract »  |  Full Text »  |  PDF »

Regulation of Expression of Phospholipase D1 and D2 by PEA-15, a Novel Protein That Interacts with Them.

Y. Zhang, O. Redina, Y. M. Altshuller, M. Yamazaki, J. Ramos, H. Chneiweiss, Y. Kanaho, and M. A. Frohman (2000)
J. Biol. Chem. 275, 35224-35232
 |  Abstract »  |  Full Text »  |  PDF »

ADVERTISEMENT

To Advertise   |   Find Products