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Vol. 16, Issue 7, 3301-3313, July 2005

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Dynamin Forms a Src Kinase–sensitive Complex with Cbl and Regulates Podosomes and Osteoclast Activity

Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, CT 06510

Submitted December 27, 2004; Revised April 11, 2005; Accepted April 26, 2005
Monitoring Editor: Paul Matsudaira

Podosomes are highly dynamic actin-containing adhesion structures found in osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of osteoclasts and that dynamin forms a complex with Cbl in osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in osteoclasts was decreased by Src tyrosine kinase activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased osteoclast bone resorbing activity and migration, whereas overexpression of dynK44A decreased osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in osteoclast adhesion, migration, and resorption.

Abbreviations used: IP, immunoprecipitate; mRIPA, modified radioimmune precipitation assay; OCL, osteoclast-like cell; VnR, vitronectin receptor; GTP, guanosine 5' triphosphate; GED, GTPase effector domain; PTB, phosphotyrosine-binding domain; PRD, proline-rich domain. PH, pleckstrin homology; PBS, phosphate buffered saline; FCS, fetal calf serum.

^* Present address: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140.

Address correspondence to: Angela Bruzzaniti (angela.bruzzaniti{at}yale.edu).

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