RESCUE OF OSTEOCLAST FUNCTION BY TRANSGENIC EXPRESSION OF KINASE-DEFICIENT SRC IN SRC- - MUTANT MICE/

The Src tyrosine kinase has been implicated in a wide variety of signa l transduction pathways, yet despite the nearly ubiquitous expression of c-src, src-/-mice show only one major phenotype-osteopetrosis cause d by an intrinsic defect in osteoclasts, the cells responsible for res orbing bone. To explore further the role of Src both in osteoclasts an d other cell types, we have generated transgenic mice that express the wild-type and phosphatase (TRAP), a gene that is expressed highly in osteoclasts. We demonstrate here that expression of a wild-type transg ene in only a limited number of tissues can fully rescue the src-l-phe notype. Surprisingly, expression of kinase-defective alleles of c-src also reduces osteopetrosis in src-/-animals and partially rescues a de fect in cytoskeletal organization observed in src-l-osteoclasts. These results suggest that there are essential kinase-independent functions for Src in vivo. Biochemical examination of osteoclasts from these mi ce suggest that Src may function in part by recruiting or activating o ther tyrosine kinases.