Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
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DOI：
10.1083/jcb.200611083
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发表时间：
2007-03-12
影响因子：
7.8
通讯作者：
Teitelbaum, Steven L
中科院分区：
文献类型：
--
作者：
Zou, Wei;Kitaura, Hideki;Reeve, Jennifer;Long, Fanxin;Tybulewicz, Victor L J;Shattil, Sanford J;Ginsberg, Mark H;Ross, F Patrick;Teitelbaum, Steven L
在这项研究中，我们建立了酪氨酸激酶Syk是破骨细胞在体外和体内的功能所必需的。Syk-/-破骨细胞无法组织其细胞骨架，因此其骨吸收能力被抑制。这种缺陷导致Syk−/−胚胎的骨骼质量增加，并抑制破骨细胞缺乏激酶的嵌合小鼠的基础和刺激骨吸收。Syk缺乏对骨骼的影响反映了成熟破骨细胞活性的降低，而不是分化受损。Syk通过与αvβ3整联蛋白和c-Src结合形成信号复合物来调节骨吸收，该信号复合物仅在αvβ3活化时产生。整合素占据后，c-Src磷酸化Syk。αvβ3诱导的Syk磷酸化以及后者与c-Src结合的能力由免疫受体酪氨酸激活基序（ITAM）蛋白Dap 12和FcRγ介导。因此，Syk、c-Src和αvβ3与ITAM携带蛋白一起代表了骨吸收破骨细胞中的必需信号复合物，因此，每一种都是候选治疗靶点。
In this study, we establish that the tyrosine kinase Syk is essential for osteoclast function in vitro and in vivo. Syk−/− osteoclasts fail to organize their cytoskeleton, and, as such, their bone-resorptive capacity is arrested. This defect results in increased skeletal mass in Syk−/− embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lack the kinase. The skeletal impact of Syk deficiency reflects diminished activity of the mature osteoclast and not impaired differentiation. Syk regulates bone resorption by its inclusion with the αvβ3 integrin and c-Src in a signaling complex, which is generated only when αvβ3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. αvβ3-induced phosphorylation of Syk and the latter's capacity to associate with c-Src is mediated by the immunoreceptor tyrosine-based activation motif (ITAM) proteins Dap12 and FcRγ. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and αvβ3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.