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首页> 外文期刊>Molecular and Cellular Biology >Spatial Localization of m-Calpain to the Plasma Membrane by Phosphoinositide Biphosphate Binding during Epidermal Growth Factor Receptor-Mediated Activation
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Spatial Localization of m-Calpain to the Plasma Membrane by Phosphoinositide Biphosphate Binding during Epidermal Growth Factor Receptor-Mediated Activation

机译：在表皮生长因子受体介导的活化过程中，磷酸肌醇双磷酸酯结合使m-钙蛋白酶在血浆膜上的空间定位。

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Calpain activity is required for de-adhesion of the cell body and rear to enable productive locomotion of adherent cells during wound repair and tumor invasion. Growth factors activate m-calpain (calpain 2, CAPN2) via ERK/mitogen-activated protein kinases, but only when these kinases are localized to the plasma membrane. We thus hypothesized that m-calpain is activated by epidermal growth factor (EGF) only when it is juxtaposed to the plasma membrane secondary to specific docking. Osmotic disruption of NR6 fibroblasts expressing the EGF receptor demonstrated m-calpain being complexed with the substratum-adherent membrane with this increasing in an EGF-dependent manner. m-Calpain colocalized with phosphoinositide biphosphate (PIP2) with exogenous phospholipase C removal of phosphoinositides, specifically, PI(4,5)P2 but not PI(4)P1 or PIP3, releasing the bound m-calpain. Downregulation of phosphoinositide production by 1-butanol resulted in diminished PIP2 in the plasma membrane and eliminated EGF-induced calpain activation. This PIP2-binding capacity resided in domain III of calpain, which presents a putative C2-like domain. This active conformation of this domain appears to be partially masked in the holoenzyme as both activation of m-calpain by phosphorylation at serine 50 and expression of constitutively active phosphorylation mimic glutamic acid-increased m-calpain binding to the membrane, consistent with blockade of this cascade diminishing membrane association. Importantly, we found that m-calpain was enriched toward the rear of locomoting cells, which was more pronounced in the plasma membrane footprints; EGF further enhanced this enrichment, in line with earlier reports of loss of PIP2 in lamellipodia of motile cells. These data support a model of m-calpain binding to PIP2 concurrent with and likely to enable ERK activation and provides a mechanism by which cell de-adhesion is directed to the cell body and tail as phospholipase C-γ hydrolyzes PIP2 in the protruding lamellipodia.
机译：钙蛋白酶活性对于细胞体和后部的去粘连是必需的，以使贴壁细胞在伤口修复和肿瘤侵袭过程中能够高效移动。生长因子通过ERK /促分裂原激活的蛋白激酶激活m-钙蛋白酶（钙蛋白酶2，CAPN2），但仅当这些激酶位于质膜上时才激活。因此，我们假设仅当将m-钙蛋白酶与特定对接的次要质膜并置时才被表皮生长因子（EGF）激活。表达EGF受体的NR6成纤维细胞的渗透破坏表明m-钙蛋白酶与基质粘附膜形成复合物，并以EGF依赖性方式增加。 m-钙蛋白酶与磷酸肌醇双磷酸酯（PIP 2 ）共定位，并通过外源磷脂酶C去除磷酸肌醇，特别是PI（4,5）P 2 ，而不是PI（4）P 1 或PIP 3 ，释放结合的m-钙蛋白酶。 1-丁醇下调磷酸肌醇的产生导致质膜中PIP 2 减少，并消除了EGF诱导的钙蛋白酶激活。这种PIP 2 的结合能力位于钙蛋白酶的结构域III中，该结构域是一个假定的C2样结构域。该结构域的这种活性构象似乎在全酶中被部分掩盖了，既通过丝氨酸50的磷酸化激活m-钙蛋白酶，又表达了组成型活性磷酸化模拟谷氨酸增加了与膜的m-钙蛋白酶结合，这与该酶的阻断相一致。级联递减的膜结合。重要的是，我们发现m-钙蛋白酶在机车细胞的后部富集，这在质膜足迹中更为明显。 EGF进一步增强了这种富集，这与早期报道的运动细胞板脂膜中PIP 2 丢失有关。这些数据支持m-钙蛋白酶与PIP 2 结合并同时可能激活ERK的模型，并提供了一种机制，通过该机制，细胞去粘连作为磷脂酶C-直接导向细胞体和尾巴。 γ水解突出的片状脂膜中的PIP 2 。

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