Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity.
Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity.
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DOI：
10.1002/jcp.22861
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发表时间：
2012-04
影响因子：
5.6
通讯作者：
Halevy, O.
中科院分区：
文献类型：
--
作者：
Madhala-Levy, D.;Williams, V. C.;Hughes, S. M.;Reshef, R.;Halevy, O.
Sonic hedgehog（Shh）可促进成肌细胞的增殖和分化，并通过Smothened（Smo）影响Akt的磷酸化。在这里，Shh和IGF-I之间的关系进行了检查，通过信号通路，调节这一过程的肌源性分化。每种因子均以剂量反应方式增强Akt和MAPK/ERK（p42/44）磷酸化和生肌因子表达水平，而Shh和IGF-I的组合显示出累加效应。通过中和抗体阻断IGF-I的作用部分降低了Shh对信号传导途径的作用，表明IGF-I增强了Shh的作用，但不是必需的。添加Smo抑制剂环巴胺以类似的方式减少Shh和IGF-I诱导的Akt磷酸化，这意味着Shh影响IGF-I信号通路的获得。这种影响也通过遗传学方法进行了研究。在来自Smomut（MCre;Smoflox/flox）小鼠的培养物中，与IGF-I对Smo细胞的作用相比，IGF-I诱导的Akt和p42/44磷酸化显著降低，Smo表达在后肢肌肉中特异性缺失。此外，在Smomut培养物中观察到IGF-I对成肌分化的刺激作用的显着抑制，这意味着完整的Smo是成肌细胞中IGF-I作用所必需的。免疫沉淀试验表明，p-Tyr蛋白，包括PI 3 K（p85）的调节单元，被招募到Smo响应Shh。此外，IGF-IR被发现与Smo响应Shh和IGF-I，这表明Shh和IGF-I已经在受体水平整合，这是一种机制，通过这种机制，它们的信号通路相互作用，增强它们对成人成肌细胞的影响。
Sonic hedgehog (Shh) has been shown to promote adult myoblast proliferation and differentiation and affect Akt phosphorylation via its effector Smoothened (Smo). Here, the relationship between Shh and IGF-I was examined with regard to myogenic differentiation via signaling pathways which regulate this process. Each factor enhanced Akt and MAPK/ERK (p42/44) phosphorylation and myogenic factor expression levels in a dose-responsive manner, while combinations of Shh and IGF-I showed additive effects. Blockage of the IGF-I effects by neutralizing antibody partially reduced Shh’s effects on signaling pathways, suggesting that IGF-I enhances, but is not essential for Shh effects. Addition of cyclopamine, a Smo inhibitor, reduced Shh- and IGF-I-induced Akt phosphorylation in a similar manner, implying that Shh affects gain of the IGF-I signaling pathway. This implication was also examined via a genetic approach. In cultures derived from Smomut (MCre;Smoflox/flox) mice lacking Smo expression specifically in hindlimb muscles, IGF-I-induced Akt and p42/44 phosphorylation was significantly reduced compared to IGF-I’s effect on Smocont cells. Moreover, remarkable inhibition of the stimulatory effect of IGF-I on myogenic differentiation was observed in Smomut cultures, implying that intact Smo is required for IGF-I effects in myoblasts. Immunoprecipitation assays revealed that p-Tyr proteins, including the regulatory unit of PI3K (p85), are recruited to Smo in response to Shh. Moreover, IGF-IR was found to associate with Smo in response to Shh and to IGF-I, suggesting that Shh and IGF-I are already integrated at the receptor level, a mechanism by which their signaling pathways interact in augmenting their effects on adult myoblasts.
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影响因子：
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作者：
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