Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism

PEA-15 is a small, death effector-domain (DED)-containing protein that was recently demonstrated to inhibit tumor necrosis factor-alpha-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. Surprisi...

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Bibliographic Details
Published in:Molecular biology of the cell 2000-09, Vol.11 (9), p.2863-2872
Main Authors: Ramos, J W, Hughes, P E, Renshaw, M W, Schwartz, M A, Formstecher, E, Chneiweiss, H, Ginsberg, M H
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Cell Adhesion
Cell Line
CHO Cells
Cricetinae
Enzyme Activation
Guanosine Triphosphate - metabolism
Humans
Intracellular Signaling Peptides and Proteins
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 1
Mice
Mitogen-Activated Protein Kinases - metabolism
p38 Mitogen-Activated Protein Kinases
Phosphoproteins - metabolism
Protein-Serine-Threonine Kinases - metabolism
ras Proteins - metabolism
Recombinant Fusion Proteins - metabolism
Signal Transduction
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Summary:PEA-15 is a small, death effector-domain (DED)-containing protein that was recently demonstrated to inhibit tumor necrosis factor-alpha-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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.11.9.2863