Cross-talk between the calcium-sensing receptor and the epidermal growth factor receptor in Rat-1 fibroblasts
- University of Michigan Medical School, Ann Arbor, MI 48109 (United States)
- Biological Sciences Division, Battelle for the US DOE, PO Box 999, 790 Sixth Street, Richland, WA 99352 (United States)
The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that is activated by extracellular calcium (Ca {sub o} {sup 2+}). Rat-1 fibroblasts have been shown to proliferate and increase ERK activity in response to elevation of [Ca{sup 2+}] {sub o}, and these responses are dependent on functional CaR expression. In this report, we examined the role of cross-talk between the CaR and the epidermal growth factor receptor (EGFR) in mediating these responses in Rat-1 cells. This report shows that AG1478, a specific inhibitor of the EGFR kinase, significantly inhibits the increase in proliferation induced by elevated Ca {sub o} {sup 2+}. Furthermore, we show that AG1478 acts downstream or separately from G protein subunit activation of phospholipase C. AG1478 significantly inhibits Ca {sub o} {sup 2+}-stimulated ERK phosphorylation and in vitro kinase activity. A similar inhibition of ERK phosphorylation was observed in response to the inhibitor AG494. In addition, treatment with inhibitors of metalloproteases involved in shedding of membrane anchored EGF family ligands substantially inhibited the increase in ERK activation in response to elevated Ca {sub o} {sup 2+}. This is consistent with the known expression of TGF{alpha} by Rat-1 cells. These results indicate that EGFR transactivation is an important component of the CaR-mediated response to increased Ca {sub o} {sup 2+} in Rat-1 fibroblasts and most likely involves CaR-mediated induction of regulated proteolysis and ligand shedding.
- OSTI ID:
- 20717645
- Journal Information:
- Experimental Cell Research, Vol. 308, Issue 2; Other Information: DOI: 10.1016/j.yexcr.2005.04.032; PII: S0014-4827(05)00217-X; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
Similar Records
A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor
Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor alpha