Editors' ChoiceMAPK PATHWAY

Ras Rids Raf of IMP

Science's STKE  20 Jan 2004:
Vol. 2004, Issue 216, pp. tw25-TW25
DOI: 10.1126/stke.2162004TW25

The small guanosine triphosphatase Ras, which is activated by environmental stimuli, has been implicated in oncogenic transformation through stimulation of the Raf-mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK signaling pathway. Matheny et al. identified IMP (impedes mitogenic signal propagation) as a protein that interacted with Ras in a two-hybrid screen and demonstrated coimmunoprecipitation of IMP with activated Ras in various cells. The authors analyzed the downstream effects of IMP transfection on the MAPK pathway and determined that IMP blocked Raf activation of MEK1 and MEK2. Depletion of IMP with small interfering RNA increased the response of the MAPK cascade to mitogen stimulation in human epithelial cells and fibroblasts and enhanced the morphological response of PC12 cells to nerve growth factor. Structural analysis indicated that IMP contained a RING-H2 domain, which suggests that it might function as an E3 ubiquitin ligase. Consistent with this, an in vitro assay indicated that IMP could polyubiquitinate itself. High-molecular-mass IMP species were also detected in cells expressing activated Ras and IMP. Expression of ligase-defective IMP blocked Ras-dependent phosphorylation of extracellular signal-regulated kinase (ERK). Endogenous IMP associated with endogenous KSR (kinase suppressor of Ras, a scaffolding protein implicated in Raf interaction with MEK) and IMP expression promoted phosphorylation of KSR, mimicking the effects of a KSR loss-of-function mutant. Moreover, IMP-dependent inhibition of ERK required KSR expression. Thus, IMP appears to inhibit Raf activation of MEK through a mechanism involving KSR, and Ras appears not only to activate Raf, but to inactivate IMP, an inhibitor of Raf signaling, by stimulating its auto-ubiquitination.

S. A. Matheny, C. Chen, R. Kortum, G. L. Razidio, R. E. Lewis, M. A. White, Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256-260 (2004). [Online Journal]