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Tyrosine Phosphorylation Regulates Alpha II Spectrin Cleavage by Calpain

机译：酪氨酸磷酸化调节钙蛋白酶对αII血影蛋白的裂解。

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Spectrins, components of the membrane skeleton, are implicated in various cellular functions. Understanding the diversity of these functions requires better characterization of the interacting domains of spectrins, such as the SH3 domain. Yeast two-hybrid screening of a kidney cDNA library revealed that the SH3 domain of αII-spectrin binds specifically isoform A of low-molecular-weight phosphotyrosine phosphatase (LMW-PTP). The αII-spectrin SH3 domain does not interact with LMW-PTP B or C nor does LMW-PTP A interact with the αI-spectrin SH3 domain. The interaction of spectrin with LMW-PTP A led us to look for a tyrosine-phosphorylated residue in αII-spectrin. Western blotting showed that αII-spectrin is tyrosine phosphorylated in vivo. Using mutagenesis on recombinant peptides, we identified the residue Y1176 located in the calpain cleavage site of αII-spectrin, near the SH3 domain, as an in vitro substrate for Src kinase and LMW-PTP A. This Y1176 residue is also an in vivo target for kinases and phosphatases in COS cells. Phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro. Similarly, the presence of phosphatase inhibitors in cell culture is associated with the absence of spectrin cleavage products. This suggests that the Y1176 phosphorylation state could modulate spectrin cleavage by calpain and may play an important role during membrane skeleton remodeling.
机译：光谱是膜骨架的组成部分，与多种细胞功能有关。了解这些功能的多样性需要更好地表征蛋白相互作用域，例如SH3域。酵母双杂交筛选肾脏cDNA文库显示，αII-血影蛋白的SH3结构域特异性结合低分子量磷酸酪氨酸磷酸酶（LMW-PTP）的同工型A。 αII-血影蛋白SH3结构域不与LMW-PTP B或C相互作用，LMW-PTP A也不与αI-血影蛋白SH3结构域相互作用。血影蛋白与LMW-PTP A的相互作用促使我们寻找αII-血影蛋白中酪氨酸磷酸化的残基。 Western印迹表明，αII-血影蛋白在体内被酪氨酸磷酸化。通过对重组肽的诱变，我们确定了位于αII-Spectrin的钙蛋白酶切割位点，SH3域附近的残基Y1176作为Src激酶和LMW-PTP A的体外底物。该Y1176残基也是体内靶标用于COS细胞中的激酶和磷酸酶。该残基的磷酸化降低了血影蛋白对钙蛋白酶的体外敏感性。类似地，细胞培养物中磷酸酶抑制剂的存在与血影蛋白裂解产物的缺乏有关。这表明Y1176的磷酸化状态可以调节钙蛋白酶对血影蛋白的裂解，并可能在膜骨架重塑中发挥重要作用。

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