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Submitted on January 24, 2002
Accepted on April 30, 2003
Stimulated MAP kinase activation in cultured TMOb Murine Osteoblasts
1 The Geriatrics Research, Education and Clinical Center, Durham Veterans Affairs Medical Center and the Department of Medicine, Duke University Medical Center, Durham, NC., Department of Medicine, University of Wisconsin-Madison, Madison, WI., Department of Medicine, Thomas Jefferson University, Philadelphia, PA
* To whom correspondence should be addressed. E-mail: luttrell{at}receptor-biol.duke.edu.
Recent data suggest that G protein-coupled receptors (GPCRs), including those for PTH (PTH) and prostaglandins, contribute to the proliferation and differentiation of osteoblasts in vivo. To understand how these signals are transduced, we studied activation of the ERK1/2 mitogen-activated protein (MAP) kinase cascade in cultures of differentiating TMOb murine osteoblasts. In TMOb cells, stimulation of endogenous Gs/Gq-coupled PTH receptors, Gq-coupled Prostanglandin F2
receptors, and Gi/Gq-coupled lysophosphatidic acid receptors, but not Gs-coupled Prostaglandin E2 receptors, caused a rapid five- to ten-fold increase in ERK1/2 phosphorylation. GPCR-stimulated ERK1/2 activation coincided with increased tyrosine phosphorylation of epidermal growth factor (EGF) receptors, and was blocked by the EGF receptor inhibitor, tyrphostin AG1478 and the metalloprotease inhibitor, batimastat, suggesting that the response involved transactivation of EGF receptors through the proteolytic release of an EGF receptor ligand. To further examine the mechanism of PTH-stimulated EGF receptor transactivation, we employed COS-7 cells expressing the rat PTH receptor. Here, stimulation with PTH(1-34) caused proteolysis of HA epitope-tagged heparin binding-EGF, increased tyrosine autophosphorylation of EGF receptors, and AG1478-sensitive ERK1/2 activation. When PTH receptor-expressing COS-7 cells were placed in a mixed culture with cells lacking the PTH receptor but expressing a green fluorescent protein-tagged ERK2 (GFP-ERK2), stimulation with PTH(1-34) induced phosphorlyation of GFP-ERK2 that was abolished by either batimastat or tyrphostin AG1478. These data suggest that autocrine/paracrine cross talk between EGF receptors and Gi- or Gq/11-coupled GPCRs represents the predominant mechanism of GPCR-mediated activation of ERK1/2 in cultured TMOb osteoblasts.
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