The Molecular Scaffold KSR1 Regulates the Proliferative and Oncogenic Potential of Cells

Abstract

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.

We thank Charles Kuszynski and Linda Wilkie in the UNMC Cell Analysis Facility for their technical expertise in the generation of GFP-expressing cell lines and Eric Gosink and Thomas Smithgall for retroviral vectors. We also thank Gina Razidlo for her critical reading of the manuscript and members of the Lewis lab for their insights and advice.

This research was supported by NIH grants CA90400 and DK52809, the Charlotte Geyer Foundation, the American Diabetes Association (R.E.L.), and grant CA36727-19 to the UNMC/Eppley Cancer Center. R.L.K. was supported by a physician/scientist training fellowship from the American Diabetes Association.