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

Abstract

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.

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system

“…This raises the possibility that other alterations in BRAF may drive the activation of p-MAPK1 and CDKN2A in pilocytic astrocytoma of the optic nerve. Alternatively, alterations in negative regulatory factors of the MAPK pathway, such as the Sprouty family of proteins, Raf kinase inhibitor protein, impedes mitogenic signal propagation, and the (7) 10 (16) dual-specificity MAPK phosphatase [29][30][31][32][33][34][35][36] may be found in pilocytic astrocytoma of the optic nerve. Studies are currently under way to test for these possibilities.…”

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

“…At the same time, they exclude other related components that operate in parallel cascades, insulating a MAPK module from undesired interferences. [77] In addition, scaffolds play important roles in the spatial selectivity of ERK signals: KSR1 acts preferentially upon ERK signals emanating from PM cholesterol-rich domains; [78] MP-1 regulates ERK in endosomes; [79] Sef at the GC; [80] and Paxillin at focal adhesions. [81] b-Arrestins are abundant in clathrin-coated pits.…”

p21 Ras/Impedes Mitogenic Signal Propagation Regulates Cytokine Production and Migration in CD4 T Cells

“…It has been proposed that BRAP2 masks nuclear localization signal motifs causing the mislocalization of specific nuclear proteins and thus serving as a cytoplasmic retention protein (29,30). Interestingly, White and collaborators (28) demonstrated that Imp can also disrupt the Ras/ERK pathway possibly by uncoupling Raf kinase from MEK through the inactivation of a scaffolding protein of the Ras pathway called the kinase suppressor of Ras (KSR). The exact mechanism of this inhibition of KSR function is unknown, however.…”

“…It is not surprising to find therefore that T cells and other cell types have developed inhibitors to control the magnitude and duration of the ERK signaling. Among the most prominent endogenous repressors of the Ras/ERK signaling are GTPase-activating proteins (18,19), downstream of tyrosine kinase (Dok) adaptor proteins (20 -22), members of the Sprouty protein family (23,24), diacylglycerol kinases (DGK-and DGK-␣) (25,26), ERK-specific dual specificity phosphatases (27), and a molecule with an E3 ubiquitin ligase activity described recently as impedes mitogenic signal propagation (Imp) (28).…”