Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival.
Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival.
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DOI：
10.1101/gad.840301
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发表时间：
2001-01
影响因子：
10.5
通讯作者：
Lianping Xing;Ana M. Venegas;Amy Chen;Lisa Garrett-Beal;Brendan F. Boyce;Harold E. Varmus;P. Schwartzberg
中科院分区：
文献类型：
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作者：
Lianping Xing;Ana M. Venegas;Amy Chen;Lisa Garrett-Beal;Brendan F. Boyce;Harold E. Varmus;P. Schwartzberg
突变的src（-/-）小鼠患有由破骨细胞（吸收骨的细胞）缺陷引起的骨硬化症。然而，涉及Src家族成员在破骨细胞中的信号通路仍不清楚。我们证明，表达一个截短的Src分子，Src 251，缺乏激酶结构域，诱导骨石症的野生型和src（+/-）小鼠和骨石症的src（-/-）小鼠通过一种新的机制，增加破骨细胞凋亡。Src 251诱导细胞凋亡需要一个功能性的SH 2结构域，而不是SH 3结构域，并且与AKT激酶活性降低有关。Src 251的表达显著降低了破骨细胞对RANKL/TRANCE/OPGL的反应，提供了Src家族激酶是TNF家族受体下游生存信号通路所需的体内证据。
Mutant src(-/-) mice have osteopetrosis resulting from defective osteoclasts, the cells that resorb bone. However, signaling pathways involving Src family members in osteoclasts remain unclear. We demonstrate that expression of a truncated Src molecule, Src251, lacking the kinase domain, induces osteopetrosis in wild-type and src(+/-) mice and worsens osteopetrosis in src(-/-) mice by a novel mechanism, increased osteoclast apoptosis. Induction of apoptosis by Src251 requires a functional SH2, but not an SH3, domain and is associated with reduced AKT kinase activity. Expression of Src251 dramatically reduces osteoclast survival in response to RANKL/TRANCE/OPGL, providing evidence that Src family kinases are required in vivo for survival signaling pathways downstream from TNF family receptors.