Protein tyrosine phosphatase Shp2 positively regulates cold stress-induced tyrosine phosphorylation of SIRPα in neurons
Protein tyrosine phosphatase Shp2 positively regulates cold stress-induced tyrosine phosphorylation of SIRPα in neurons
复制标题
蛋白酪氨酸磷酸酶Shp2正向调节神经元中冷应激诱导的SIRPα酪氨酸磷酸化
DOI：
10.1016/j.bbrc.2021.06.084
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发表时间：
2021
影响因子：
3.1
通讯作者：
Ohnishi Hiroshi
中科院分区：
文献类型：
--
作者：
Jingu Daiki;Iino Mika;Kawasaki Joji;Urano Eriko;Kusakari Shinya;Hayashi Yuriko;Matozaki Takashi;Ohnishi Hiroshi
膜蛋白 SIRPα 是神经元中的冷应激反应信号分子。冷应激直接诱导细胞质区域SIRPα酪氨酸磷酸化，磷酸化的SIRPα参与调节小鼠经验依赖性行为变化。在这里，我们在体外和体内研究了冷应激诱导的 SIRPα 磷酸化的机制。降低培养神经元的温度不会增加激活的 Src 家族蛋白酪氨酸激酶 (SFK)（磷酸化 SIRPα）的水平。尽管 SFK 抑制剂达沙替尼显着降低了 SIRPα 磷酸化，但即使存在达沙替尼，低温也会诱导 SIRPα 磷酸化增加，这表明低温诱导的 SIRPα 磷酸化不需要 SFK 激活。然而，在过钒酸盐（蛋白酪氨酸磷酸酶 (PTPases) 的有效抑制剂）存在的情况下，SIRPα 磷酸化通过降低温度而显着降低，这表明使 SIRPα 去磷酸化的 PTPase 失活或增加对磷酸化 SIRPα 免受 PTPase 活性的保护对于低温诱导的 SIRPα 磷酸化非常重要。变构 Shp2 抑制剂 SHP099 使 PTPase Shp2 失活，但竞争性抑制剂 NSC-87877 不会使 PTPase Shp2 失活，从而降低培养神经元中 SIRPα 的磷酸化。 Shp2 敲除还降低了小鼠大脑中 SIRPα 的磷酸化。我们的数据表明，Shp2（而非 SFK）以不依赖于 PTPase 活性的方式正向调节冷应激诱导的 SIRPα 磷酸化。
The membrane protein SIRPα is a cold stress-responsive signaling molecule in neurons. Cold stress directly induces tyrosine phosphorylation of SIRPα in its cytoplasmic region, and phosphorylated SIRPα is involved in regulating experience-dependent behavioral changes in mice. Here, we examined the mechanism of cold stress-induced SIRPα phosphorylation in vitro and in vivo. The levels of activated Src family protein tyrosine kinases (SFKs), which phosphorylate SIRPα, were not increased by lowering the temperature in cultured neurons. Although the SFK inhibitor dasatinib markedly reduced SIRPα phosphorylation, low temperature induced an increase in SIRPα phosphorylation even in the presence of dasatinib, suggesting that SFK activation is not required for low temperature-induced SIRPα phosphorylation. However, in the presence of pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases), SIRPα phosphorylation was significantly reduced by lowering the temperature, suggesting that either the inactivation of PTPase(s) that dephosphorylate SIRPα or increased protection of phosphorylated SIRPα from the PTPase activity is important for low temperature-induced SIRPα phosphorylation. Inactivation of PTPase Shp2 by the allosteric Shp2 inhibitor SHP099, but not by the competitive inhibitor NSC-87877, reduced SIRPα phosphorylation in cultured neurons. Shp2 knockout also reduced SIRPα phosphorylation in the mouse brain. Our data suggest that Shp2, but not SFKs, positively regulates cold stress-induced SIRPα phosphorylation in a PTPase activity-independent manner.