The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells.
The specificity of signaling through mitogen-activated protein kinase pathways has been attributed to both the control of intensity and duration of signaling and the actions of protein scaffolds. Here we demonstrate that the molecular scaffold KSR1 regulates the intensity and duration of ERK activation to modulate a cell's proliferative and oncogenic potential. Deletion of KSR1 eliminates the prolonged phase of ERK activation induced by platelet-derived growth factor and blocks Ras(V12)-induced transformation. The introduction of KSR1 into KSR1(-/-) mouse embryo fibroblasts causes a concentration-dependent increase in signaling and transformation, to a maximum at 14 times the wild-type KSR1 expression levels, but inhibits these responses at higher expression levels. An increase in KSR1 expression to levels that are optimal for signaling leads to a threefold increase in proliferative capacity and is coincident with the level of KSR1 expression that maximally associates with all members of the Raf/MEK/ERK cascade. These data reveal that cells contain a reserve proliferative capacity that is accessible by the optimal expression of a noncatalytic signaling component and that altering the expression level of a molecular scaffold can modulate the actions of growth factors and oncogenes.
Kortum
Robert L
RL
Eppley Institute for Cancer Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Lewis
Robert E
RE
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D011905:Genes, ras; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D011494:Protein Kinases; C097199:KSR-1 protein kinase