A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK

  title={A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK},
  author={Damian F. Brennan and Arvin C. Dar and Nicholas T Hertz and William Chong Hang Chao and Alma L. Burlingame and Kevan M. Shokat and David Barford},
In metazoans, the Ras–Raf–MEK (mitogen-activated protein-kinase kinase)–ERK (extracellular signal-regulated kinase) signalling pathway relays extracellular stimuli to elicit changes in cellular function and gene expression. Aberrant activation of this pathway through oncogenic mutations is responsible for a large proportion of human cancer. Kinase suppressor of Ras (KSR) functions as an essential scaffolding protein to coordinate the assembly of Raf–MEK–ERK complexes. Here we integrate… 

Targeting oncogenic Raf protein-serine/threonine kinases in human cancers.

MEK drives BRAF activation through allosteric control of KSR proteins

It is demonstrated that KSR–MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts and challenge the accepted role of KSR as a scaffold for MEK recruitment to RAF.

MEK1/2 dual-specificity protein kinases: structure and regulation.

  • R. Roskoski
  • Biology
    Biochemical and biophysical research communications
  • 2012

Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling

Con conformational switching in KSR is revealed as a druggable regulator of oncogenic Ras, and co-targeting of enzymatic and scaffolding activities within Ras–MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers is suggested.

Complexity in KSR function revealed by Raf inhibitor and KSR structure studies

The newly solved KSR2/MEK1 structure has revealed important mechanistic details for how KSR regulates MEK activation and has raised questions regarding KSR kinase activity, and KSR1 attenuates the paradoxical activating effect of these drugs on ERK signaling.

Structural snapshots of RAF kinase interactions.

This review focuses on structural understanding of how distinct binding partners trigger a cascade of molecular events that induces RAF kinase activation.

Ras-Mediated Activation of the Raf Family Kinases.

The current understanding of how Ras promotes Raf activation is examined, focusing on the molecular mechanisms that contribute to the Raf activation/inactivation cycle.

Tyr728 in the Kinase Domain of the Murine Kinase Suppressor of RAS 1 Regulates Binding and Activation of the Mitogen-activated Protein Kinase Kinase*

It is proposed that phosphorylation of Tyr728 may regulate the transition between the scaffolding and catalytic function of KSR1 serving as a control point used to fine-tune cellular responses.

The mechanism of activation of MEK1 by B-Raf and KSR1

The results reveal that the proline-rich (P-rich) loop ofMEK1 plays a decisive role in MEK1 activation loop (A-loop) phosphorylation, and postulate that if KSR1 were to adopt an active configuration with an extended A-loop as seen in other protein kinases, then the MEK 1 P-rich loop would extend in a similar manner, as seenin the active B-Raf/MEK 1 heterodimer.

praja2 regulates KSR1 stability and mitogenic signaling

It is shown that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells.



A dimerization-dependent mechanism drives RAF catalytic activation

It is demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which is term the side-to-side dimer, and it is found that the RAF-related pseudo-kinase KSR also participates in forming side- to-side heterodimers with RAF and can thereby trigger RAF activation.

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.

Signaling dynamics of the KSR1 scaffold complex

This work identifies a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and finds that MEK binding and residues in the K SR1 CA1 region enable KSR 1 to form a ternary complex with B-Raf and MEk following growth factor treatment that enhances MEK activation.

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

X-ray structures of human MEK1 and MEK2 are presented, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 Å and 3.2 Å, and reveal a novel, noncompetitive mechanism for protein kinase inhibition.

Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF

The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk‐1 phosphorylation from MAP kinase activation

It is demonstrated that KSR is capable of uncoupling the MAP kinase activation from its target phosphorylation, and thus provide a novel mechanism for modulating the Ras–MAP kinase signaling pathway.

KSR stimulates Raf-1 activity in a kinase-independent manner.

It is found that murine KSR (mKSR1) translocates from the cytoplasm to the plasma membrane in the presence of activated Ras, revealing another point of regulation for Ras-mediated signal transduction and defining a noncatalytic role for mK SR1 in the multistep process of Raf-1 activation.