KSR Plays CRAF-ty

  title={KSR Plays CRAF-ty},
  author={Fumin Shi and Mark A. Lemmon},
  pages={1043 - 1044}
A scaffold protein has enzymatic activity that controls a major cell signaling pathway. Organization of the bewildering array of known cell signaling proteins into coherent networks is facilitated by “scaffold” proteins that guide local information flow by binding multiple signaling molecules (1). Recent studies on one such scaffold protein called kinase suppressor of RAS (KSR), however, blur distinctions between the scaffold and the “scaffolded” by indicating that KSR itself has enzymatic… 
A pickup in pseudokinase activity.
  • A. Dar
  • Biology, Chemistry
    Biochemical Society transactions
  • 2013
The purpose of the present review is to summarize several of the active pseudokinases, and one in particular termed KSR (kinase suppressor of Ras), which was recently found to possess a kinase activity that can become accelerated through an allosteric mechanism.
Signalling scaffolds and local organization of cellular behaviour
The features of scaffold proteins are examined and examples of locally organized groups of signalling enzymes that drive essential physiological processes, including hormone action, heart rate, cell division, organelle movement and synaptic transmission are highlighted.
JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships
Because upstream signaling components impact JNK activity, this work critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway.
Structural Analysis of Ras Bound to Raf Kinase and Implications of Ras Allosteric Site
From these findings, it is seen that the allosteric site influences the conformation of the residues at the active site of Ras, and one way to deactivate Ras is explored by a mechanism of intrinsic hydrolysis.
Src Homology 2 Domain-containing Phosphatase 2 (Shp2) Is a Component of the A-kinase-anchoring Protein (AKAP)-Lbc Complex and Is Inhibited by Protein Kinase A (PKA) under Pathological Hypertrophic Conditions in the Heart*
It is demonstrated that the tyrosine phosphatase, Shp2, is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex and that AKAP-Lbc-associated Shp 2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation.
Signaling by Non-Canonical Receptor Tyrosine Kinases ERBB3 and RYK
The work described in this dissertation attempts to understand the non-canonical signaling by ErbB3 and Ryk/Derailed using a combination of biophysical, biochemical and cell biology methods and tries to understand, for the first time, the molecular mechanism of Ryk-Wnt interaction using Drl as a model system.


Scaffold Proteins: Hubs for Controlling the Flow of Cellular Information
Although most scaffolds use a simple tethering mechanism to increase the efficiency of interaction between individual partner molecules, these proteins can also exert complex allosteric control over their partners and are themselves the target of regulation.
Pseudokinases-remnants of evolution or key allosteric regulators?
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.
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.
Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF
  • Jiancheng Hu, Haiyang Yu, A. Shaw
  • Biology
    Proceedings of the National Academy of Sciences
  • 2011
This work suggests that KSR1 may function as a kinase, and it is anticipated that the mutation generated may be broadly applicable to stabilize the closed conformation of other kinases many of which may also form dimers.
Mechanistic principles of RAF kinase signaling
The RAF family of kinases are key components acting downstream of receptor tyrosine kinases and cells employ several distinct mechanisms to strictly control their activity, and the multitude of regulatory protein–protein interactions involving RAF remains a largely untapped area for therapeutic applications.
ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation
It is reported here that, despite sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region—although it is substantially less active than EGFR and does not phosphorylate exogenous peptides.
Drug discovery: Inhibitors that activate
Inhibitors of RAF enzymes can suppress or activate the same signalling pathway and provide a cautionary note for those targeting the pathway for anticancer drug discovery.