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First published online 12 July 2005
doi: 10.1242/jcs.02436
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Research Article |
-dependent signal to ERK1/2 activated by Vß3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells
1 Department of Experimental Medicine, University of L'Aquila, via Vetoio - Coppito 2, 67100, L'Aquila, Italy
2 Department of Cell Biology and Orthopedics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
3 ProSkelia SAS, 102 route de Noisy, 93230 Romainville, France
Author for correspondence (e-mail: teti{at}univaq.it)
Accepted 11 May 2005
We identified a novel protein kinase C (PKC)
-dependent signal to extracellular signal-regulated kinase (ERK)1/2 in mouse osteoclasts and Chinese hamster ovary (CHO) cells, specifically activated by the Vß3 integrin. It involves translocation (i.e. activation) of PKC from the cytosol to the membrane and/or the Triton X-100-insoluble subcellular fractions, with recruitment into a complex with Vß3 integrin, growth factor receptor-bound protein (Grb2), focal adhesion kinase (FAK) in CHO cells and proline-rich tyrosine kinase (PYK2) in osteoclasts. Engagement of vß3 integrin triggered ERK1/2 phosphorylation, but the underlying molecular mechanism was surprisingly independent of the well known Shc/Ras/Raf-1 cascade, and of phosphorylated MAP/ERK kinase (MEK)1/2, so far the only recognized direct activator of ERK1/2. In contrast, PKC was involved in ERK1/2 activation because inhibition of its activity prevented ERK1/2 phosphorylation. The tyrosine kinase c-Src also contributed to ERK1/2 activation, however, it did not interact with PKC in the same molecular complex. The Vß3/PKC complex formation was fully dependent upon the intracellular calcium concentration ([Ca2+]i), and the use of the intracellular Ca2+ chelator 1,2-bis(o-amino-phenoxy)ethane-N,N,N',N'-tetraaceticacidtetra (acetoxymethyl) ester (BAPTA-AM) also inhibited PKC translocation and ERK1/2 phosphorylation. Functional studies showed that Vß3 integrin-activated PKC was involved in cell migration and osteoclast bone resorption, but had no effect on the ability of cells to attach to LM609, suggesting a role in events downstream of Vß3 integrin engagement.
Key words: osteoclasts, Vß3 integrin, PKC, c-Src, ERK1/2
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