The Role of KSR-Associated Kinases in Breast Cancer Signaling
Abstract
Kinase Suppressor of Ras (KSR) is a putative scaffold of the Raf/MEK/ERK kinase cascade. This kinase cascade is critical for the proliferation of malignant breast carcinomas. We have examined the effect of phosphorylation and protein-protein interaction on the subcellular distribution and biological activity of KSR. KSR is phosphorylated on at least 15 residues in intact cells. This phosphorylation is due to KSR-associated kinases and not due to autophosphorylation by the KSR kinase domain. Mutation of KSR phosphorylation sites reveals that phosphorylation of Ser392 and Thr274 potently inhibits the translocation of KSR from cytoplasm to nucleus. When R589M or C809Y mutations are introduced into KSR they prevent nuclear localization of KSR inhibit the interaction of KSR with MEK, but enhance ERK activation and RasV12-induced anchorage-independent growth. Nuclear targeting of KSR by mutation of Ser392 and Thr274, or by the addition of the SV40 nuclear localization signal (NLS), does not alter the biological activity of intact KSR. However, addition of an NLS to KSR.C809Y accelerates cell proliferation in culture. These data suggest that the ability of KSR to affect cell proliferation and transformation is a function of its phosphorylation state, its interaction with MEK and its nucleocytoplasmic distribution.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2003
- Accession Number
- ADA413743
Entities
People
- Robert E Lewis
- Steven J. Schreiner
Organizations
- University of Nebraska Medical Center