Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice
Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice
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DOI：
10.1101/gad.11.21.2835
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发表时间：
1997-11-01
影响因子：
10.5
通讯作者：
Varmus, HE
中科院分区：
文献类型：
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作者：
Schwartzberg, PL;Xing, LP;Varmus, HE
Src酪氨酸激酶参与了多种信号转导途径，尽管c-src几乎无处不在，但src-/-小鼠仅表现出一种主要表型-由破骨细胞（负责吸收骨的细胞）的内在缺陷引起的骨石化症。为了进一步探索Src在破骨细胞和其他细胞类型中的作用，我们已经产生了表达野生型和磷酸酶（TRAP）的转基因小鼠，TRAP是一种在破骨细胞中高度表达的基因。我们在这里证明，野生型转基因的表达，只有有限数量的组织可以完全拯救src-1-表型。令人惊讶的是，c-src的激酶缺陷型等位基因的表达也减少了src-/-动物中的石骨症，并部分挽救了在src-1-破骨细胞中观察到的细胞骨架组织缺陷。这些结果表明，有必要的激酶不依赖功能的Src在体内。从这些小鼠破骨细胞的生化检查表明，Src的功能可能部分通过招募或激活其他酪氨酸激酶。
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 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-l-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-l-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.