ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts |
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Authors: | V Fortino C Torricelli C Gardi G Valacchi S Rossi Paccani E Maioli |
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Institution: | (1) Department of Physiology , US;(2) Department of Physiopathology and Experimental Medicine , US;(3) CCRBM Department of Internal Medicine, University of California Davis, Surge I - Room 1121, Davis, California 95616 (USA), US;(4) Laboratory of Molecular Biology, Department of Evolutionary Biology University of Siena, via Aldo Moro, 53100 Siena (Italy), Fax + 39 577 234219, e-mail: maioli@unisi.it, IT |
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Abstract: | Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. |
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Keywords: | , PTHrP, fibroblast, proliferation, PKA, PKC, MAPK, |
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