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 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.
Xing
L
L
Department of Pathology, University of Rochester, Rochester, New York 14627, USA.
Venegas
A M
AM
Chen
A
A
Garrett-Beal
L
L
Boyce
B F
BF
Varmus
H E
HE
Schwartzberg
P L
PL
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002470:Cell Survival; D002645:Chickens; D017931:DNA Primers / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt