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Vol. 273, Issue 2, 1114-1120, January 9, 1998
From the Department of Cell and Developmental Biology, Oregon
Health Sciences University, Portland, Oregon 97201-3098
Changes in the concentration of extracellular
calcium can affect the balance between proliferation and
differentiation in several cell types, including keratinocytes, breast
epithelial cells, and fibroblasts. This report demonstrates that
elevation of extracellular calcium stimulates proliferation-associated
signaling pathways in rat fibroblasts and implicates calcium-sensing
receptors (CaR) as mediators of this response. Rat-1 fibroblasts
express CaR mRNA and protein and respond to known agonists of the
CaR with increased IP3 production and release of
intracellular calcium. Agonists of the CaR can stimulate increased
c-SRC kinase activity and increased extracellular signal-regulated
kinase 1/mitogen-activated protein kinase activity. Both of the
increases in SRC activity and mitogen-activated protein kinase
activation are blocked in the presence of a nonfunctional mutant of the
CaR, R796W. Proliferation of wild-type Rat-1 cells is sensitive to
changes in extracellular calcium, but expression of the nonfunctional
CaR mutant or inhibition of the calcium-dependent increase
in SRC kinase activity block the proliferative response to calcium.
These results provide evidence of a novel signal transduction pathway
modulating the response of fibroblasts to extracellular calcium and
imply that calcium-sensing receptors may play a role in regulating cell
growth in response to extracellular calcium, in addition to their well
known function in systemic calcium homeostasis.
Functional Calcium-sensing Receptors in Rat Fibroblasts Are
Required for Activation of SRC Kinase and Mitogen-activated Protein
Kinase in Response to Extracellular Calcium
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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