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J. Biol. Chem., Vol. 283, Issue 19, 12789-12796, May 9, 2008

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IMP Modulates KSR1-dependent Multivalent Complex Formation to Specify ERK1/2 Pathway Activation and Response Thresholds^*

Chiyuan Chen, Robert E. Lewis, and Michael A. White¹

From the Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and the Eppley Institute for Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68198-9805

The Ras effector and ubiquitin-protein isopeptide ligase family member IMP acts as a steady-state resistor within the Raf-MEK-ERK kinase module. IMP concentrations are regulated by Ras through induction of autodegradation and can modulate signal/response thresholds by directly limiting the assembly of functional KSR1-dependent Raf·MEK complexes. Here, we show that the capacity of IMP to inhibit signal propagation through Raf to MEK is a consequence of disrupting KSR1 homooligomerization and B-Raf/c-Raf hetero-oligomerization. This impairs both the recruitment of MEK to activated Raf family members and the contribution of Raf oligomers to c-Raf kinase activation. Our observations indicate that human KSR1 proteins promote assembly of multivalent Raf·MEK complexes that are required for c-Raf kinase activation and functional coupling of active kinases to downstream substrates. This property is engaged by IMP for modulation of signal amplitude.

Received for publication, November 13, 2007 , and in revised form, March 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA71443 from NCI. This work was also supported by Grant I-1414 from the Robert Welch Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390. Tel.: 214-648-2861; Fax: 214-648-8694; E-mail: michael.white{at}utsouthwestern.edu.

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