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

  title={Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP},
  author={Sharon A. Matheny and Chiyuan Chen and Robert L. Kortum and Gina L. Razidlo and Robert E. Lewis and Michael A. White},
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… 

IMP Modulates KSR1-dependent Multivalent Complex Formation to Specify ERK1/2 Pathway Activation and Response Thresholds*

The Ras effector and ubiquitin-protein isopeptide ligase family member IMP acts as a steady-state resistor within the Raf-MEK-ERK kinase module and impairs both the recruitment of MEK to activated Raf family members and the contribution of Raf oligomers to c-Raf kinase activation.

Signaling Threshold Regulation by the Ras Effector IMP*

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.

The role of scaffold proteins in MEK/ERK signalling.

  • D. Sacks
  • Biology
    Biochemical Society transactions
  • 2006
The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.

Effectors of Ras-Mediated Oncogenesis

Recent findings of mutational activation of B-Raf in human cancers are summarized and the importance of non-Rafa effectors in Ras-mediated signaling and transformation is examined.

Calmodulin influences MAPK signaling by binding KSR1

RAS and the RAF/MEK/ERK Cascade

The Raf/MEK/ERK protein kinases constitute a key effector cascade used by Ras to relay signals regulating cell growth, survival, proliferation, and differentiation, allowing sensitive activation and deactivation of the pathway in response to diverse extracellular cues.

AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade

It is demonstrated that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2.

The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells.

  • J. Ramos
  • Biology
    The international journal of biochemistry & cell biology
  • 2008



Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module and competitively disrupts the interaction between these kinases.

Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo

KSR is a bona fide scaffold that is not required for but enhances signaling via the Ras/MAPK signaling pathway, and high-molecular-weight complexes containing KSR, MEK, and ERK were lost in the absence of KSR.

KSR is a scaffold required for activation of the ERK/MAPK module.

It is suggested that KSR functions as a scaffold that assembles the RAF/MEK functional pair, and that these interactions lead to the formation of a RAF/ MEK complex, thereby positioning RAF in close proximity to its substrate MEK.

Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase.

It is shown that Raf-1 and Ras cooperate in trans-activation through the oncogene-responsive element and that the cysteine-rich region is necessary for this effect.

Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling

Raf-1 residues 338 to 341 constitute a unique phosphoregulatory site in which the phosphorylation of serine and tyrosine residues contributes to the regulation of Raf by Ras, Src, and Ras-independent membrane localization.

Phosphorylation Regulates the Nucleocytoplasmic Distribution of Kinase Suppressor of Ras*

The data indicate that the subcellular distribution of KSR is dynamically regulated through phosphorylation and MEK interaction in a manner that may affect signaling through ERK.

Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways.

We demonstrate the efficacy of double-stranded RNA-mediated interference (RNAi) of gene expression in generating "knock-out" phenotypes for specific proteins in several Drosophila cell lines. We

Multiple ras functions can contribute to mammalian cell transformation