Working Without Kinase Activity: Phosphotransfer-Independent Functions of Extracellular Signal–Regulated Kinases

ERK2 plays kinase-independent roles in chromatin remodeling, gene transcription, and cell cycle regulation. Extracellular signal–regulated kinase 1 (ERK1) and ERK2 are typical serine and threonine kinases that are members of the family of mitogen-activated protein kinases and are involved in the regulation of key cellular processes, including proliferation, differentiation, and survival, through the phosphorylation of nearly 200 substrates. However, accumulating evidence demonstrates that ERK1 and ERK2 can also function independently of their kinase activities in the control of critical biochemical and biological events, such as chromatin remodeling, DNA transcription, and cell cycle regulation. In this Review, which contains 1 figure and 72 references, we summarize findings from a number of studies that underline the importance of these kinase-independent roles of the ERKs. The mitogen-activated protein kinases (MAPKs) extracellular signal–regulated kinase 1 (ERK1) and ERK2 play well-characterized roles in the regulation of key cellular processes, such as proliferation, differentiation, and survival, by acting as serine and threonine kinases in the phosphorylation of ~200 substrates that are distributed in different subcellular localizations. However, over the past few years, evidence has mounted that indicates that the mechanism of action of ERK1 and ERK2 may extend beyond their role as canonical kinases. For example, proteins such as poly(ADP-ribose) polymerase 1, topoisomerase II, and MAPK phosphatase 3 (MKP-3) are activated by a direct interaction with ERK2 that does not involve any phosphotransfer activity. In addition, ERK2 binds to DNA and acts as a transcriptional regulator independently of its function as a kinase. Moreover, other studies demonstrate that ERK1 and ERK2 can regulate cell cycle entry by disrupting the interaction between the retinoblastoma pocket protein and lamin A in a kinase-independent fashion. These findings strongly support the notion that ERK1 and ERK2 can play functionally important roles independently of their regular catalytic activities and provide the basis for a new perspective from which to view these hitherto archetypical signaling kinases.

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