The β3 integrin cytoplasmic domain, and specifically S752, is critical for integrin localization and osteoclast (OC) function. Because growth factors such as macrophage colony–stimulating factor and hepatocyte growth factor affect integrin activation and function via inside-out signaling, a process requiring the β integrin cytoplasmic tail, we examined the effect of these growth factors on OC precursors. To this end, we retrovirally expressed various β3 integrins with cytoplasmic tail mutations in β3-deficient OC precursors. We find that S752 in the β3 cytoplasmic tail is required for growth factor–induced integrin activation, cytoskeletal reorganization, and membrane protrusion, thereby affecting OC adhesion, migration, and bone resorption. The small GTPases Rho and Rac mediate cytoskeletal reorganization, and activation of each is defective in OC precursors lacking a functional β3 subunit. Activation of the upstream mediators c-Src and c-Cbl is also dependent on β3. Interestingly, although the FAK-related kinase Pyk2 interacts with c-Src and c-Cbl, its activation is not disrupted in the absence of functional β3. Instead, its activation is dependent upon intracellular calcium, and on the β2 integrin. Thus, the β3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function.
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4 August 2003
Article|
August 04 2003
Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin
Roberta Faccio,
Roberta Faccio
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
3Department of Human Anatomy, School of Medicine, 70124 Bari, Italy
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Deborah V. Novack,
Deborah V. Novack
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
2Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Alberta Zallone,
Alberta Zallone
3Department of Human Anatomy, School of Medicine, 70124 Bari, Italy
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F. Patrick Ross,
F. Patrick Ross
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
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Steven L. Teitelbaum
Steven L. Teitelbaum
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
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Roberta Faccio
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
3Department of Human Anatomy, School of Medicine, 70124 Bari, Italy
Deborah V. Novack
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
2Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
Alberta Zallone
3Department of Human Anatomy, School of Medicine, 70124 Bari, Italy
F. Patrick Ross
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
Steven L. Teitelbaum
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
Address correspondence to Steven L. Teitelbaum, Department of Pathology, Washington University School of Medicine, 216 South Kingshighway, St. Louis, MO 63110. Tel.: (314) 454-8463. Fax: (314) 454-5505. email: [email protected]
The online version of this article includes supplemental material.
Abbreviations used in this paper: BMM, bone marrow macrophage; HGF, hepatocyte growth factor; LIBS, ligand-induced binding site; M-CSF, macrophage colony–stimulating factor; OC, osteoclast; OPN, osteopontin; VN, vitronectin.
Received:
December 17 2002
Accepted:
June 12 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 162 (3): 499–509.
Article history
Received:
December 17 2002
Accepted:
June 12 2003
Citation
Roberta Faccio, Deborah V. Novack, Alberta Zallone, F. Patrick Ross, Steven L. Teitelbaum; Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin . J Cell Biol 4 August 2003; 162 (3): 499–509. doi: https://doi.org/10.1083/jcb.200212082
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