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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Base Sequence
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Cell Survival
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Chickens
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DNA Primers / genetics
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Mice
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Mice, Knockout
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Mice, Transgenic
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Osteoclasts / pathology
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Osteopetrosis / genetics
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Osteopetrosis / pathology
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Tumor Necrosis Factor / genetics*
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction
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src Homology Domains
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src-Family Kinases / chemistry
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src-Family Kinases / genetics*
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src-Family Kinases / metabolism*
Substances
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DNA Primers
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Proto-Oncogene Proteins
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Receptors, Tumor Necrosis Factor
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src-Family Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt