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Graded inhibition of oncogenic Ras-signaling by multivalent Ras-binding domains.


ABSTRACT: BACKGROUND: Ras is a membrane-associated small G-protein that funnels growth and differentiation signals into downstream signal transduction pathways by cycling between an inactive, GDP-bound and an active, GTP-bound state. Aberrant Ras activity as a result of oncogenic mutations causes de novo cell transformation and promotes tumor growth and progression. RESULTS: Here, we describe a novel strategy to block deregulated Ras activity by means of oligomerized cognate protein modules derived from the Ras-binding domain of c-Raf (RBD), which we named MSOR for multivalent scavengers of oncogenic Ras. The introduction of well-characterized mutations into RBD was used to adjust the affinity and hence the blocking potency of MSOR towards activated Ras. MSOR inhibited several oncogenic Ras-stimulated processes including downstream activation of Erk1/2, induction of matrix-degrading enzymes, cell motility and invasiveness in a graded fashion depending on the oligomerization grade and the nature of the individual RBD-modules. The amenability to accurate experimental regulation was further improved by engineering an inducible MSOR-expression system to render the reversal of oncogenic Ras effects controllable. CONCLUSION: MSOR represent a new tool for the experimental and possibly therapeutic selective blockade of oncogenic Ras signals.

SUBMITTER: Augsten M 

PROVIDER: S-EPMC3898410 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Graded inhibition of oncogenic Ras-signaling by multivalent Ras-binding domains.

Augsten Martin M   Böttcher Anika A   Spanbroek Rainer R   Rubio Ignacio I   Friedrich Karlheinz K  

Cell communication and signaling : CCS 20140102


<h4>Background</h4>Ras is a membrane-associated small G-protein that funnels growth and differentiation signals into downstream signal transduction pathways by cycling between an inactive, GDP-bound and an active, GTP-bound state. Aberrant Ras activity as a result of oncogenic mutations causes de novo cell transformation and promotes tumor growth and progression.<h4>Results</h4>Here, we describe a novel strategy to block deregulated Ras activity by means of oligomerized cognate protein modules d  ...[more]

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