Sci. STKE, 20 August 2002
MAPK Two Paths from Ras to ERK
Mitogen-activated protein kinase (MAPK) signaling leads to the activation and nuclear translocation of the terminal kinase in the pathway extracellular signal-regulated kinase (ERK), of which there aretwo isoforms, ERK1 and ERK2. ERKs are activated by phosphorylation by an upstream kinase MEK1 or MEK2. ERK2 mutants that could not bind MEK1 or MEK2 were phosphorylated and activated with similar kinetics and to a similar extent as was wild-type ERK2 when the cells were stimulated with growth factors, suggesting that the basal complex between MEK and ERK2 is not required for signaling through the pathway. However, when the MAPK pathway was activated by expression of a constitutively activated form of MEK1, bypassing the multiple signals that are initiated by an activated growth factor receptor, the MEK-binding mutants of ERK2 were not phosphorylated efficiently. MEK1 could not phosphorylate the ERK2 mutants in vitro either. Inhibition of Ras signaling blocked phosphorylation of the ERK2 mutants in response to growth factors and a constitutively active mutant of Ras stimulated phosphorylation of the mutant ERK2s. Activated forms of Rac and Cdc42 promoted the interaction between wild-type ERK2 and MEK1, but neither of these activated guanosine triphosphatases (GTPases) led to the formation of a detectable complex between the ERK2 mutants and MEK1. Mutation of the two PAK1 phosphorylation sites on MEK1 inhibited Rac-induced MEK1-ERK2 complex formation. MEK2 lacks the consensus PAK1 phosphorylation sites and the interaction between MEK2 and ERK2 is not influenced by activation of Rac. Kinase-defective PAK1 inhibited the MEK1-ERK2 interaction and inhibited ERK2 phosphorylation in response to cell adhesion on fibronectin. Thus, there appears to be a Rac-stimulated interaction, mediated by PAK1 phosphorylation of MEK1, between MEK1 and ERK2 that may explain how signals can converge to activate ERK2 and how MEK1 and MEK2 isoforms may differentially regulate ERK activation.
S. T. Eblen, J. K. Slack, M. J. Weber, A. D. Catling, Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol. Cell. Biol. 22, 6023-6033 (2002). [Abstract] [Full Text]
Citation: Two Paths from Ras to ERK. Sci. STKE 2002, tw305 (2002).
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