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Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP
Sharon A Matheny1, Chiyuan Chen, Robert L Kortum
1Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039, USA.
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.
Insights
The Ras effector protein Impedes Mitogenic signal Propagation (IMP) regulates the sensitivity of the MAP kinase cascade. IMP inactivation enhances MEK activation, acting as a threshold modulator for cellular signaling.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Oncogenesis
Background:
- The Raf-MEK-MAP kinase cascade is a critical Ras effector pathway involved in cellular responses and oncogenic transformation.
- KSR acts as a scaffold protein, facilitating the interaction between Raf and MEK within this cascade.
Purpose of the Study:
- To investigate the role of the Ras effector protein Impedes Mitogenic signal Propagation (IMP) in modulating the MAP kinase cascade.
- To elucidate the mechanism by which IMP controls the sensitivity and activation of the Raf-MEK-MAP kinase pathway.
Main Methods:
- Investigated the interaction between IMP, KSR, Raf, and MEK.
- Utilized auto-polyubiquitination assays to study IMP's E3 ubiquitin ligase activity.
- Assessed MEK activation upon IMP depletion in response to stimuli.
Main Results:
- IMP is a Ras-responsive E3 ubiquitin ligase that inactivates KSR, thereby limiting Raf-MEK complex formation.
- Ras activation leads to IMP auto-polyubiquitination, releasing KSR inhibition and enabling Raf-MEK complex assembly.
- Depletion of IMP enhances stimulus-dependent MEK activation without affecting response timing or duration.
Conclusions:
- IMP functions as a threshold modulator, controlling the sensitivity of the MAP kinase cascade to external stimuli.
- IMP's mechanism allows for adaptive signaling behavior in complex or chronic signaling environments.
- The dual action of Ras, activating Raf kinase and derepressing Raf-MEK complex formation via IMP, is crucial for MAP kinase cascade activation.
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