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

IEX‐1 is an early response and NF‐κB 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.