title: 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.
  
  
  CONCLUSIONS
  MSOR represent a new tool for the experimental and possibly therapeutic selective blockade of oncogenic Ras signals.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden. Martin.Augsten@ki.se.
authors.forename: Martin
authors.initials: M
authors.lastname: Augsten
authors.forename: Anika
authors.initials: A
authors.lastname: Böttcher
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanbroek
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Friedrich
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins