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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.
Scaffold proteins contribute to the spatiotemporal control ofMAPK signaling and KSR1 is an ERK cascade scaffold that localizesto 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 cascadecomponents, Raf, MEK, and ERK. Here, we identify a hydrophobicmotif within the proline-rich sequence (PRS) of MEK1 and MEK2that is required for constitutive binding to KSR1 and find thatMEK binding and residues in the KSR1 CA1 region enable KSR1to form a ternary complex with B-Raf and MEK following growthfactor treatment that enhances MEK activation. We also findthat docking of active ERK to the KSR1 scaffold allows ERK tophosphorylate KSR1 and B-Raf on feedback S/TP sites. Strikingly,feedback phosphorylation of KSR1 and B-Raf promote their dissociationand result in the release of KSR1 from the plasma membrane.Together, these findings provide unique insight into the signalingdynamics of the KSR1 scaffold and reveal that through regulatedinteractions with Raf and ERK, KSR1 acts to both potentiateand attenuate ERK cascade activation, thus regulating the intensityand duration of ERK cascade signaling emanating from the plasmamembrane 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.