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Molecular and Cellular Biology, June 2008, p. 3610-3622, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.00259-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phospholipase C{gamma}2 Modulates Integrin Signaling in the Osteoclast by Affecting the Localization and Activation of Src Kinase{triangledown} ,{dagger}

Holly Epple,1,2,{ddagger} Viviana Cremasco,3,{ddagger} Kaihua Zhang,3 Dailing Mao,3 Gregory D. Longmore,1,2* and Roberta Faccio2,3*

Departments of Medicine,1 Cell Biology,2 Orthopedics, Washington University, St. Louis, Missouri3

Received 14 February 2008/ Accepted 21 March 2008

Integrin engagement induces a cascade of signaling pathways that include tyrosine phosphorylation of numerous proteins that lead to modulation of the actin cytoskeleton. Src is a major intracellular mediator of integrin-dependent functions, but the mechanism(s) by which Src is regulated in response to integrin signals is not fully understood. Here, we demonstrate an important role for phospholipase C gamma 2 (PLC{gamma}2) in Src activation in the osteoclast. Through analysis of primary cells from PLC{gamma}2–/– mice, PLC{gamma}2 was found to be an important regulator of {alpha}vβ3 integrin-mediated bone osteoclast cell adhesion, migration, and bone resorption. Adhesion-induced PYK2 and Src phosphorylation is decreased in the absence of PLC{gamma}2, and the interaction of Src with β3 integrin and PYK2 is dramatically reduced. Importantly, PLC{gamma}2 was found to be required for proper localization of Src to the sealing actin ring, and this function required both its catalytic activity and adapter domains. Based on these results, we propose that PLC{gamma}2 influences Src activation by mediating the localization of Src to the integrin complex and thereby regulating integrin-mediated functions in the osteoclast.

* Corresponding author. Mailing address for Roberta Faccio: Washington University School of Medicine, Department of Orthopedics, 660 South Euclid, Campus Box 8233, St. Louis, MO 63110. Phone: (314) 747-4602. Fax: (314) 362-0334. E-mail: faccior{at}wudosis.wustl.edu. Mailing address for Gregory Longmore: Washington University School of Medicine, Division of Hematology, 660 S. Euclid Ave., Campus Box 8125, St. Louis, MO 63110. Phone: (314) 362-8834. Fax: (314) 362-8826. E-mail: glongmor{at}im.wustl.edu

{triangledown} Published ahead of print on 31 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to the work.

Molecular and Cellular Biology, June 2008, p. 3610-3622, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.00259-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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