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Sci. Signal., 14 July 2009
Vol. 2, Issue 79, p. ec235
[DOI: 10.1126/scisignal.279ec235]

EDITORS' CHOICE

Biochemistry ERK Breaks Up Ménage à Trois at the Plasma Membrane

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

The mitogen-activated protein kinase (MAPK) signaling pathway provides an example of the remarkably subtle and elaborate controls that are necessary on a cellular control module that regulates a huge range of processes from proliferation and survival to metabolism and cell motility. The molecules of the MAPK cascade—the protein kinase Raf, which phosphorylates another kinase, MEK, which in turn phosphorylates the MAPK ERK—are localized in signaling complexes by scaffold proteins, increasing the efficiency of their interaction and stipulating the specificity and localization of such events. McKay et al. report that the choreography of interaction of these proteins with the scaffold KSR1 (kinase suppressor of Ras 1) is more intricate than previously appreciated. KSR was identified as a positive regulator of the small guanosine triphosphatase Ras, which initiates activation of Raf and the rest of the MAPK cascade. The authors looked more closely at the interactions of these proteins and provide evidence that in response to signals from growth factor receptors, KSR1 forms a ternary complex with B-Raf and MEK. This promotes activation of ERK, and activation of ERK exposes a binding site that allows ERK to also interact with KSR1, where it phosphorylates four sites on each of the KSR1 and B-Raf proteins. If the binding site for ERK on KSR1 was disrupted, or the sites that ERK phosphorylates on KSR1 were mutated, though, interaction of KSR with Raf1 was enhanced and signaling was prolonged. Thus, the authors conclude that ERK provides a negative feedback signal that actually disrupts interaction of B-Raf and KSR1 and releases KSR1 from the cell membrane, thereby adjusting the intensity and duration of signaling through the MAPK cascade.

M. M. McKay, D. A. Ritt, D. K. Morrison, Signaling dynamics of the KSR1 scaffold complex. Proc. Natl. Acad. Sci. U.S.A. 106, 11022–11027 (2009). [Abstract] [Full Text]

Citation: L. B. Ray, ERK Breaks Up Ménage à Trois at the Plasma Membrane. Sci. Signal. 2, ec235 (2009).


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