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PNAS 106 (27): 11022-11027

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Signaling dynamics of the KSR1 scaffold complex

Melissa M. McKay, Daniel A. Ritt, and Deborah K. Morrison1

Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute-Frederick, P. O. Box B, Frederick, MD 21702

Received for publication February 12, 2009.

Abstract: Scaffold proteins contribute to the spatiotemporal control of MAPK signaling and KSR1 is an ERK cascade scaffold that localizes to the plasma membrane in response to growth factor treatment. To better understand the molecular mechanisms of KSR1 function, we examined the interaction of KSR1 with each of the ERK cascade components, Raf, MEK, and ERK. Here, we identify a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and find that MEK binding and residues in the KSR1 CA1 region enable KSR1 to form a ternary complex with B-Raf and MEK following growth factor treatment that enhances MEK activation. We also find that docking of active ERK to the KSR1 scaffold allows ERK to phosphorylate KSR1 and B-Raf on feedback S/TP sites. Strikingly, feedback phosphorylation of KSR1 and B-Raf promote their dissociation and result in the release of KSR1 from the plasma membrane. Together, these findings provide unique insight into the signaling dynamics of the KSR1 scaffold and reveal that through regulated interactions with Raf and ERK, KSR1 acts to both potentiate and attenuate ERK cascade activation, thus regulating the intensity and duration of ERK cascade signaling emanating from the plasma membrane during growth factor signaling.

Key Words: ERK cascade • protein scaffolds • signal tranduction

Edited by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, and approved May 13, 2009

Author contributions: M.M.M., D.A.R., and D.K.M. designed research; M.M.M., D.A.R., and D.K.M. performed research; M.M.M., D.A.R., and D.K.M. analyzed data; and M.M.M. and D.K.M. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0901590106/DCSupplemental.

1To whom correspondence should be addressed. E-mail: dmorrison{at}ncifcrf.gov

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