Signaling threshold regulation by the Ras effector IMP

Abstract

The Ras effector and E3 ligase family member IMP (impedes mitogenic signal propagation) acts as a steady-state resistor within the Raf-MEK-ERK kinase module. IMP concentrations are directly regulated by Ras, through induction of autoubiquitination, to permit productive Raf-MEK complex assembly. Inhibition of Raf-MEK pathway activation by IMP occurs through the inactivation of KSR, a scaffold/adapter protein that couples activated Raf to its substrate MEK1. The capacity of IMP to inhibit signal propagation through Raf to MEK is, in part, a consequence of disrupting KSR1 homo-oligomerization and c-Raf-B-Raf hetero-oligomerization. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus by directly limiting the assembly of functional KSR1-dependent Raf-MEK complexes.

FIGURE 1.

IMP impedes Ras mitogenic signaling by limiting KSR1 complexes. In the absence of mitogen, IMP blocks KSR1 C-terminal homo-oligomerization (Step 1), KSR1-c-Raf binding (Step 2), B-Raf-MEK binding without affecting their association with KSR1 (Step 3), and B-Raf-c-Raf hetero-oligomerization (Step 4). Upon stimulation, Ras-GTP binds IMP and activates its autoubiquitination, thus relieving signal inhibition. Concomitantly, Ras-GTP activates Raf and allows subsequent KSR1 complex formation and ERK pathway signaling.