Lp. Xing et al., Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival, GENE DEV, 15(2), 2001, pp. 241-253
Mutant src(-/-) mice have osteopetrosis resulting from defective osteoclast
s, the cells that resorb bone. However, signaling pathways involving Src fa
mily members in osteoclasts remain unclear. We demonstrate that expression
of a truncated Src molecule, Src251, lacking the kinase domain, induces ost
eopetrosis in wild-type and src(+/-) mice and worsens osteopetrosis in src(
-/-) mice by a novel mechanism, increased osteoclast apoptosis. Induction o
f apoptosis by Src251 requires a functional SH2, but not an SH3, domain and
is associated with reduced ART kinase activity. Expression of Src251 drama
tically reduces osteoclast survival in response to RANKL/TRANCE/OPGL, provi
ding evidence that Src family kinases are required in vivo for survival sig
naling pathways downstream from TNF family receptors.