Ras regulates MAP kinase signaling by derepressing Impedes Mitogenic signal Propagation (IMP)- induced Raf-MEK complex formation. IMP modulates the sensitivity of the MAP kinase cascade to stimulus-dependent activation.
Ras signaling regulates a variety of cellular processes and is often mutated in human cancers. The small GTPase Ras relays mitogenic signals to multiple signaling cascades. One such cascade is the Raf/MAP kinase pathway, which amongst other functions regulates the cell cycle.
Michael White's group now report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) acts as a modulator of Raf signaling by inhibiting the interaction of Raf with MAP kinase kinase (MEK). IMP is highly conserved across eukaryotes; it was first discovered in Xenopus by yeast two-hybrid analysis using Ras as bait. In the present study, IMP was expressed together with an oncogenic variant of Raf (RafBXB). The results show that IMP blocks Raf-induced activation of endogenous MEK and ERK and consequently c-Fos transcription. However, Ras activity remains unaffected by IMP expression. IMP blocks the interaction of Raf1 with MEK1 and MEK2, via inhibition of the KSR adaptor/scaffold protein. The group shows that depletion of IMP fails to increase ERK activation. Further, they demonstrate that IMP is an E3 ubiquitin ligase that auto-polyubiquitinates upon Ras activation, though the consequence of this is unclear. Altogether, this implies a mechanism whereby mitogenic signals activate Ras, leading to inhibition of IMP and subsequent Raf-MEK complex formation.
These findings reveal that Ras elicits a simultaneous dual effector mechanism on MAP kinase signaling: it induces Raf kinase activity, while derepressing Raf-MEK complex formation. This may allow for the fine-tuning of this central mitogenic signaling pathway in a complex environment.
Julia Howlett, Assistant Editor Assistant Editor, Signaling Gateway
References
Matheny, Sharon A. Chen, Chiyuan Kortum, Robert L. Razidlo, Gina L. Lewis, Robert E. White, Michael A. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP.
Nature427 256–260
(15 January 2004) 10.1038/nature02237 | PubMed |
