IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation.

IEX-1 is an early response and NF-kappaB target gene implicated in the regulation of cellular viability. We show here that IEX-1 is a substrate for ERKs and that IEX-1 and ERK regulate each other's activities. IEX-1 was isolated by phosphorylation screening with active ERK2 and found subsequently phosphorylated in vivo ...
upon ERK activation. IEX-1 interacts with phosphorylated ERKs but not with c-jun N-terminal kinase (JNK) or p38. Upon phosphorylation by ERKs, IEX-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, IEX-1 potentiates ERK activation in response to various growth factors. By using various IEX-1 mutants in which the ERK phosphoacceptor and/or ERK docking sites were mutated, we show that the IEX-1 pro-survival effect is dependent on its phosphorylation state but not on its ability to potentiate ERK activation. Conversely, IEX-1-induced modulation of ERK activation requires ERK-IEX-1 association but is independent of IEX-1 phosphorylation. Thus, IEX-1 is a new type of ERK substrate that has a dual role in ERK signaling by acting both as an ERK downstream effector mediating survival and as a regulator of ERK activation.
Mesh Terms:
Apoptosis Regulatory Proteins, Cell Death, Cell Line, Cell Survival, Enzyme Activation, Gene Library, Glutathione Transferase, Humans, Immediate-Early Proteins, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Neoplasm Proteins, Phosphorylation, Recombinant Fusion Proteins, Substrate Specificity, Tumor Cells, Cultured
EMBO J.
Date: Oct. 01, 2002
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