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 signal transduction pathways, yet despite the nearly ubiquitous expression of c-src, src-/- mice show only one major phenotype-osteopetrosis caused by an intrinsic defect in osteoclasts, the cells responsible for resorbing bone. To explore further the role of Src both in osteoclasts and other cell types, we have generated transgenic mice that express the wild-type and mutated versions of the chicken c-src proto-oncogene from the promoter of tartrate resistant acid phosphatase (TRAP), a gene that is expressed highly in osteoclasts. We demonstrate here that expression of a wild-type transgene in only a limited number of tissues can fully rescue the src-/- phenotype. Surprisingly, expression of kinase-defective alleles of c-src also reduces osteopetrosis in src-/- animals and partially rescues a defect in cytoskeletal organization observed in src-/- osteoclasts. These results suggest that there are essential kinase-independent functions for Src in vivo. Biochemical examination of osteoclasts from these mice suggest that Src may function in part by recruiting or activating other tyrosine kinases.
Schwartzberg
P L
PL
National Cancer Institute, University of Texas Health Science Center, San Antonio, Texas 78284, USA. pams@mhgri.nih.gov
Xing
L
L
Hoffmann
O
O
Lowell
C A
CA
Garrett
L
L
Boyce
B F
BF
Varmus
H E
HE
D000135:Acid Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D002762:Cholecalciferol / Q000494:pharmacology; D017931:DNA Primers; D016391:Genes, src; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D000071681:Tartrate-Resistant Acid Phosphatase; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D007375:Interleukin-1; D007527:Isoenzymes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D002762:Cholecalciferol; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase