Murine Ksr interacts with MEK and inhibits Ras-induced transformation

@article{DenouelGaly1998MurineKI,
  title={Murine Ksr interacts with MEK and inhibits Ras-induced transformation},
  author={A. Denouel-Galy and Elizabeth M. J. Douville and P. H. Warne and Catherine Papin and Danielle Laugier and Georges Calothy and Julian Downward and Alain Eych{\`e}ne},
  journal={Current Biology},
  year={1998},
  volume={8},
  pages={46-55}
}
View on Elsevier
cell.com
156 Citations
Highly Influential Citations
6
Background Citations
60
Methods Citations
2
Results Citations
4

Figures from this paper

156 Citations

Epidermal Growth Factor Treatment Enhances the Kinase Activity of Kinase Suppressor of Ras*

A two-stage in vitro kinase assay is established in which KSR never comes in contact with any recombinant kinases other than c-Raf-1, showing that KSR immunoprecipitated from quiescent COS-7 cells overexpressing Flag-tagged KSR was inactive, but its activity was rapidly and markedly induced upon epidermal growth factor treatment.

KSR: a MAPK scaffold of the Ras pathway?

The model now emerging is that KSR acts as a scaffolding protein that coordinates the assembly of a membrane-localized, multiprotein MAP kinase complex, a vital step in Ras-mediated signal transduction, and while Kinase Suppressor of Ras may be its name, phosphorylation may not be its game.

Kinase Suppressor of Ras Forms a Multiprotein Signaling Complex and Modulates MEK Localization

It is shown here that two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1 loss-of-function alleles in C. elegans, suggesting that KSR may have physiological, kin enzyme-independent functions.

Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.

KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis and genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals is provided.

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.

The Kinase Activity of Kinase Suppressor of Ras1 (KSR1) Is Independent of Bound MEK*

The results of this in vitro reconstitution assay support the contention that the kinase activity of KSR1 is an intrinsic property of this protein independent of K SR1-bound endogenous MEK.

KSR and CNK: two scaffolds regulating RAS-mediated RAF activation

The possibility that KSR, a RAF-like protein, does not solely act as a scaffold, but directly induces RAF catalytic function by a kinase-independent mechanism apparently shared by RAF- like proteins is discussed.

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.

Identification of B-KSR1, a Novel Brain-Specific Isoform of KSR1 That Functions in Neuronal Signaling

Findings demonstrate the functional importance of MEK binding and indicate that B-KSR1 may function to transduce Ras-dependent signals that are required for neuronal differentiation or that are involved in the normal functioning of the mature central nervous system.

Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway.

...

References

SHOWING 1-10 OF 60 REFERENCES

The protein kinase KSR interacts with 14-3-3 protein and Raf

KSR modulates signal propagation within the MAPK cascade.

It is shown that murine KSR1 (mKSR1) cooperates with activated Ras to promote Xenopus oocyte maturation and cellular transformation and evidence that this cooperation occurs by accelerating mitogen and extracellular regulated kinase (MEK) and mitogen-activated protein Kinase (MAPK) activation.

MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events.

It is demonstrated that mek-2 acts between lin-45 raf and sur-1/mpk-1 in a signal transduction pathway used in the control of vulval differentiation and other developmental events and plays a key role in the let-60 ras-mediated vulval induction pathway.

B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222.

It is reported here that different B-Raf isoforms can be co-immunoprecipitated with anti-Mek-1 antisera in COS-1 cells and that the kinase activity of B- Raf is not required for its interaction with Mek-1.

MAP kinase pathways in yeast: For mating and more

The C. elegans ksr-1 gene encodes a novel raf-related kinase involved in Ras-mediated signal transduction

Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation

Data support the possibility that oncogenic Ras activation of Rac1 and RhoA, coupled with activation of the Raf/MAPK pathway, is required to trigger the full morphogenic and mitogenic consequences of oncogen Ras transformation.

A protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila

Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system.

It is suggested that a MEK specific sequence, not present in MAP kinase kinases which are not activated by members of the Raf family, is required for the interaction with Raf proteins, strengthening the notion that B-Raf is a stronger MEK activator than c-RAF-l.

Constitutively active mutants of MAP kinase kinase (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts.

It is concluded that the downstream elements of the growth factor signalling cascade, MAPKK-MAPK, are both necessary and sufficient to promote growth factor signals and autonomous cell cycling in fibroblasts.
...