Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP

• Published in: Nature 2004-01, Vol.427 (6971), p.256-260
• Main Authors: White, Michael A, Matheny, Sharon A, Chen, Chiyuan, Kortum, Robert L, Razidlo, Gina L, Lewis, Robert E
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; Cell physiology; Cells; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; IMP protein; Inactivation; letter; MAP Kinase Signaling System; MEK protein; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular and cellular biology; Molecular Sequence Data; multidisciplinary; Neurotransmitters; Protein Binding; Protein Kinases - genetics; Protein Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-raf - metabolism; Raf protein; ras Proteins - metabolism; Rats; Science; Science (multidisciplinary); Signal transduction; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Xenopus laevis; Xenopus Proteins - chemistry; Xenopus Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02237

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.