Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival

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 ost...

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Bibliographic Details
Published in:Genes & development 2001-01, Vol.15 (2), p.241-253
Main Authors: Xing, L, Venegas, A M, Chen, A, Garrett-Beal, L, Boyce, B F, Varmus, H E, Schwartzberg, P L
Format: Article
Language:English
Subjects:
Akt protein
Animals
Apoptosis
Base Sequence
Cell Survival
Chickens
DNA Primers - genetics
Mice
Mice, Knockout
Mice, Transgenic
Osteoclasts - pathology
osteopetrosis
Osteopetrosis - genetics
Osteopetrosis - pathology
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Receptors, Tumor Necrosis Factor - genetics
Receptors, Tumor Necrosis Factor - metabolism
Research Paper
Signal Transduction
src Homology Domains
Src protein
src-Family Kinases - chemistry
src-Family Kinases - genetics
src-Family Kinases - metabolism
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.840301