The Role of KSR-Associated Kinases in Breast Cancer Signaling
Abstract
Kinase Suppressor of Ras 1 (KSR1) is a putative scaffold of the Raf/MEK/ERK kinase cascade. Elevated activity of this mitogenic kinase cascade is a critical stimulus for the proliferation of many human cancers including malignant breast carcinomas. We examined the effects that KSR1 expression has on different cellular processes, including proliferation, cellular response to growth factor stimulation (i.e. PDGF, EGF), differentiation of fibroblasts into adipocytes, senescence, transformation by oncogenic Ras, and cell motility. The level of KSR1 expressed within cells appears to control cell fate, as very high level of KSR1 expression leads to cell proliferation and a significant reduction in cell motility, while a lower level of expression allows cells to differentiate. KSR1 therefore may serve the role of a pseudo rheostat that directs the dominant cellular processes that control cell fate. The biological mechanism of this regulation may reside in the phosphorylation of KSR1, as KSR1 is phosphorylated on at least 15 residues in intact cells, and alteration of KSR1 phosphorylation results in altered subcellular localization, enhanced activation of ERK, and increased RasV12-induced anchorage-independent growth. The exact role of KSR1 may be in the control of biological processes that regulate cytoskeletal organization, based on the findings that KSR1 can interact with three cytoskeletal modulating proteins, FHOS, FHL3, and Flightless I, and the observations that cells expressing differing levels of KSR1 show variable actin-cytoskeletal organization, cell-cell adhesion, and anchorage to the extracellular matrix. These data suggest that the scaffold protein KSR1 is intimately involved in the coordination or control of cell fate.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2004
- Accession Number
- ADA425902
Entities
People
- Robert E Lewis
- Steven J. Schreiner
Organizations
- University of Nebraska Medical Center