The goal of the proposed project is to establish the role of the calcium-sensing receptor (CaR) in regulating the proliferation of fibroblasts, and to define the signal transduction pathways interacting with the CaR. To accomplish this, Dr. Rodland's research plan has four specific aims: 1) To determine whether release of intracellular calcium is required for downstream signaling from the CaR (e.g. activation of c-Src and, ultimately, activation o ERK kinase); 2) To determine whether Src activation, Shc phosphorylation, and p62dok association with RasGAP are required for CaR-dependent activation of ERK1; 3) To determine whether Ras activation and stimulation of the Ras-Raf-Me cascade are required for CaR-dependent activation of ERK1; 4) To determine which responses to extracellular calcium are dependent on expression of the CaR, using CaR null fibroblasts generated from knock-out mice.
These aims will be accomplished through experiments using specific inhibitors and dominant negative mutants of the key participants in the hypothesized signaling pathway
| Tomlins, Scott A; Bolllinger, Nikki; Creim, Jeffrey et al. (2005) Cross-talk between the calcium-sensing receptor and the epidermal growth factor receptor in Rat-1 fibroblasts. Exp Cell Res 308:439-45 |
| Hobson, Susan A; Wright, Jay; Lee, Fred et al. (2003) Activation of the MAP kinase cascade by exogenous calcium-sensing receptor. Mol Cell Endocrinol 200:189-98 |
| Bilderback, Tim R; Lee, Fred; Auersperg, Nelly et al. (2002) Phosphatidylinositol 3-kinase-dependent, MEK- independent proliferation in response to CaR activation. Am J Physiol Cell Physiol 283:C282-8 |
| Hobson, S A; McNeil, S E; Lee, F et al. (2000) Signal transduction mechanisms linking increased extracellular calcium to proliferation in ovarian surface epithelial cells. Exp Cell Res 258:11-Jan |
