Cyclic GMP and protein kinase G control a Src-containing mechanosome in osteoblasts.
Cyclic GMP and protein kinase G control a Src-containing mechanosome in osteoblasts.
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DOI：
10.1126/scisignal.2001423
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发表时间：
2010-12-21
影响因子：
7.3
通讯作者：
Pilz RB
中科院分区：
文献类型：
--
作者：
Rangaswami H;Schwappacher R;Marathe N;Zhuang S;Casteel DE;Haas B;Chen Y;Pfeifer A;Kato H;Shattil S;Boss GR;Pilz RB
机械刺激对骨生长/重塑至关重要，流体剪切应力通过多种第二信使（包括一氧化氮（NO））促进成骨细胞的合成代谢反应，但其潜在机制尚不清楚。在这里，我们证明了NO/cGMP/PKG信号通路激活Src在机械刺激成骨细胞，启动增殖反应。PKG II是Src活化所必需的，这也需要Src与β3整联蛋白对接以及Src通过Shp-1/2磷酸酶复合物去磷酸化。PKG II直接磷酸化并刺激Shp-1活性，流体剪切应力触发PKG II、Src和Shp募集至含有β3整联蛋白的机械体。PKG II缺失小鼠显示成骨细胞Src/Erk信号传导缺陷，骨中Erk依赖性基因表达降低。我们的研究结果揭示了NO/cGMP/PKG和整合素信号之间的串扰，并建立了一个新的Src激活机制。由于Src控制Erk，Erk是成骨细胞生长和存活的关键，因此这些结果支持使用PKG激活药物作为治疗骨质疏松症的机械模拟物。
Mechanical stimulation is crucial for bone growth/remodeling, and fluid shear stress promotes anabolic responses in osteoblasts through multiple second messengers, including nitric oxide (NO), but the underlying mechanisms are not well understood. Here we demonstrate that the NO/cGMP/PKG signaling pathway activates Src in mechanically-stimulated osteoblasts, initiating a proliferative response. PKG II is necessary for Src activation, which also requires Src docking to β3 integrins and Src dephosphorylation by a Shp-1/2 phosphatase complex. PKG II directly phosphorylates and stimulates Shp-1 activity, and fluid shear stress triggers PKG II, Src, and Shp recruitment to a mechanosome containing β3 integrins. PKG II-null mice show defective osteoblast Src/Erk signaling, and decreased Erk-dependent gene expression in bone. Our findings reveal crosstalk between NO/cGMP/PKG and integrin signaling and establish a new mechanism of Src activation. Since Src controls Erk, which is key to osteoblast growth and survival, these results support use of PKG-activating drugs as mechano-mimetics for treating osteoporosis.
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影响因子：
21.3
作者：
Felsenfeld, DP;Schwartzberg, PL;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
4.1
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通讯作者：
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