Mechanistic Basis of Signal Amplitude Modulation by the Ras Effector IMP
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The RAF/MEK/MAP Kinase signal transduction cascade is the most extensively studied MAPK pathway that mediates diverse cellular responses to environmental cues, and makes a major contribution to Ras-dependent oncogenic transformation. The Ras effector and E3 ligase family member IMP (Impedes Mitogenic signal Propagation) acts as a steady-state resistor within the RAFMEK- 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 examine the mechanistic basis of signal amplitude modulation by the Ras effector IMP. We show that the capacity of IMP to inhibit signal propagation through RAF to MEK is a consequence of disrupting assembly of multivalent mitogenic complexes that are required for C-RAF kinase activation and functional coupling of active kinases to downstream substrates. We also study how Ras regulates IMP functions by isolating IMP mutants compromised for Ras interaction and how post-translational modifications such as sumoylation control IMP activities. Finally, we identify some candidate IMP binding proteins to further investigate how IMP impacts cell behaviors through protein-protein interactions and how IMP is modulated by other proteins.