A New Role for PTEN in Regulating Transient Receptor Potential Canonical Channel 6-mediated Ca2+ Entry, Endothelial Permeability, and Angiogenesis
A New Role for PTEN in Regulating Transient Receptor Potential Canonical Channel 6-mediated Ca2+ Entry, Endothelial Permeability, and Angiogenesis
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DOI：
10.1074/jbc.m110.142034
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发表时间：
2010-10-22
影响因子：
4.8
通讯作者：
Mehta, Dolly
中科院分区：
文献类型：
--
作者：
Kini, Vidisha;Chavez, Alejandra;Mehta, Dolly
磷酸酶和张力蛋白同源物（PTEN）是一种双重脂质-蛋白磷酸酶，其催化磷酸肌醇3，4，5-三磷酸转化为磷酸肌醇4，5-二磷酸，从而抑制PI 3 K-Akt依赖性细胞增殖、迁移和肿瘤血管形成。我们已经发现了一个以前未被认识的作用，PTEN在调节Ca 2+进入通过瞬时受体电位典型通道6（TRPC 6），不需要PTEN磷酸酶活性。我们表明，PTEN尾域残基394-403允许PTEN与TRPC 6缔合。炎症介质凝血酶促进这种关联。PTEN残基394-403的缺失阻止TRPC 6细胞表面表达和Ca 2+进入。然而，缺乏磷酸酶活性的PTEN突变体C124 S没有改变TRPC 6活性。凝血酶未能增加内皮细胞中的内皮单层通透性，转导Delta 394-403 PTEN突变体。有趣的是，我们还表明，凝血酶未能诱导内皮细胞迁移和管形成的细胞转导三角洲394-403 PTEN突变体。我们的研究结果表明，PTEN，通过残基394-403，作为TRPC 6的支架，使通道的细胞表面表达。通过TRPC 6的Ca 2+进入诱导内皮渗透性增加并直接促进血管生成。因此，指示PTEN发挥超出抑制PI 3 K信号传导的作用。
Phosphatase and tensin homologue (PTEN) is a dual lipid-protein phosphatase that catalyzes the conversion of phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-bisphosphate and thereby inhibits PI3K-Akt-dependent cell proliferation, migration, and tumor vascularization. We have uncovered a previously unrecognized role for PTEN in regulating Ca2+ entry through transient receptor potential canonical channel 6 (TRPC6) that does not require PTEN phosphatase activity. We show that PTEN tail-domain residues 394-403 permit PTEN to associate with TRPC6. The inflammatory mediator thrombin promotes this association. Deletion of PTEN residues 394-403 prevents TRPC6 cell surface expression and Ca2+ entry. However, PTEN mutant, C124S, which lacks phosphatase activity, did not alter TRPC6 activity. Thrombin failed to increase endothelial monolayer permeability in the endothelial cells, transducing the Delta 394-403 PTEN mutant. Paradoxically, we also show that thrombin failed to induce endothelial cell migration and tube formation in cells transducing the Delta 394-403 PTEN mutant. Our results demonstrate that PTEN, through residues 394-403, serves as a scaffold for TRPC6, enabling cell surface expression of the channel. Ca2+ entry through TRPC6 induces an increase in endothelial permeability and directly promotes angiogenesis. Thus, PTEN is indicated to play a role beyond suppressing PI3K signaling.