Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction.
Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction.
复制标题
层粘连蛋白诱导的 Rac1 和 JNKp46 激活由 Src 家族激酶启动，并模拟骨骼肌收缩的效果。
DOI：
10.1021/bi701384k
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Jarrett,HarryW
中科院分区：
文献类型：
--
作者：
Zhou,YanWen;Jiang,Daifeng;Thomason,DonaldB;Jarrett,HarryW
抗肌营养不良蛋白糖蛋白复合体中层粘连蛋白与抗肌营养不良蛋白多糖的结合可通过dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK.传递信号层粘连蛋白结合还导致合成素酪氨酸磷酸化，以启动信号传递。负责的激活剂是在这里调查的。在层粘连蛋白处理的成肌细胞、肌管或骨骼肌微粒体内，PP2和SU6656是Src家族激酶的特异性抑制剂，它们减少了磷酸酪氨酸合成素的数量，并降低了活性rac1的水平。C-Src和c-Fyn都能磷酸化合成营养素，用特定的siRNAs抑制它们中的任何一个都会降低合成营养素的磷酸化水平。当大鼠腓肠肌收缩时，RAC1的激活水平高于松弛的对照肌肉，并且RAC1与β-Dystroglan共定位。当肌肉被拉伸时，也得到了类似的结果。收缩的肌肉中还含有更多活化的c-jun氨基末端激酶JNKp46。仅含层粘连蛋白结构域LG4和LG5的表达蛋白E3可提高成肌细胞的增殖速度，而PP2则可抑制细胞的增殖。此外，在固相结合分析中，Src家族的激酶与激活的rac1和层粘连蛋白-琼脂糖共定位。因此，收缩、拉伸或层粘连蛋白结合导致Src家族激酶重新聚集到dystrophin糖蛋白复合体，激活rac1并诱导下游信号转导。DGC可能代表着骨骼肌中的机械感受器--对肌肉活动做出反应来调节肌肉的生长。SRC家族蛋白在蛋白合成中起着启动和关键作用。
Binding of laminin to dystroglycan in the dystrophin glycoprotein complex causes signaling through dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK. Laminin binding also causes syntrophin tyrosine phosphorylation to initiate signaling. The kinase responsible was investigated here. PP2 and SU6656, specific inhibitors of Src family kinases, decreased the amount of phosphotyrosine syntrophin and decreased the level of active Rac1 in laminin-treated myoblasts, myotubes, or skeletal muscle microsomes. c-Src and c-Fyn both phosphorylate syntrophin, and inhibition of either with specific siRNAs diminishes the level of syntrophin phosphorylation. When the rat gastrocnemius was contracted, the level of Rac1 activation increased compared to that of the relaxed control muscle and Rac1 colocalized with β-dystroglycan. Similar results were obtained when the muscle was stretched. Contracted muscle also contained more activated c-Jun N-terminal kinase, JNKp46. E3, an expressed protein containing only laminin domains LG4 and LG5, increased the rate of proliferation of myoblasts, and PP2 prevented cell proliferation. In addition, Src family kinases colocalized with activated Rac1 and with laminin-Sepharose in solid-phase binding assays. Thus, contraction, stretching, or laminin binding causes recruitment of Src family kinase to the dystrophin glycoprotein complex, activating Rac1 and inducing downstream signaling. The DGC likely represents a mechanoreceptor in skeletal muscle-regulating muscle growth in response to muscle activity. Src family kinases play an initiating and critical role.