Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival
Abstract
Mutant src −/− mice have osteopetrosis resulting from defective osteoclasts, the cells that resorb bone. However, signaling pathways involving Src family members in osteoclasts remain unclear. We demonstrate that expression of a truncated Src molecule, Src251, lacking the kinase domain, induces osteopetrosis in wild-type and src +/− mice and worsens osteopetrosis in src −/− mice by a novel mechanism, increased osteoclast apoptosis. Induction of apoptosis by Src251 requires a functional SH2, but not an SH3, domain and is associated with reduced AKT kinase activity. Expression of Src251 dramatically reduces osteoclast survival in response to RANKL/TRANCE/OPGL, providing evidence that Src family kinases are required in vivo for survival signaling pathways downstream from TNF family receptors.
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Footnotes
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↵4 Present address: Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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↵5 These authors contributed equally to this work.
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↵6 Corresponding author.
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E-MAIL pams{at}nhgri.nih.gov; FAX (301) 402-2170.
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Article and publication are at www.genesdev.org/cgi/doi10.1101/gad.840301.
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- Received August 1, 2000.
- Accepted November 22, 2000.
- Cold Spring Harbor Laboratory Press
