Multiple endocytic pathways of C protein-coupled receptors delineated by GIT1 sensitivity
Multiple endocytic pathways of C protein-coupled receptors delineated by GIT1 sensitivity
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DOI：
10.1073/pnas.97.3.1119
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发表时间：
2000-02-01
影响因子：
11.1
通讯作者：
Premont, RT
中科院分区：
文献类型：
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作者：
Claing, A;Perry, SJ;Premont, RT
最近，我们发现了一种gtpase激活蛋白，用于ADP核糖基化因子家族的小gtp结合蛋白，我们称之为GIT1，该蛋白最初被确定为G蛋白偶联受体激酶的相互作用伙伴，其过表达被发现影响典型β(2)-肾上腺素能受体的信号传导和内化。在这里，我们报告了GIT1过表达调节了许多（但不是全部）G蛋白偶联受体的内化。GIT1效应的特异性与受体结合的C蛋白类型无关，而与它使用的内吞途径有关。GIT1仅影响G蛋白偶联受体的功能，G蛋白偶联受体以β -抑制蛋白和动力蛋白敏感的方式通过网格蛋白包被的凹坑途径内化。此外，GIT1的作用并不局限于G蛋白偶联受体，因为该蛋白的过表达也会影响表皮生长因子受体的内化。然而，不依赖于本构激动剂的内化不受GIT1的调节，因为转铁蛋白的摄取不受GIT1过表达的影响。因此，GIT1是一种参与调节通过网格蛋白途径内化的信号受体功能的蛋白，可以作为定义受体内吞途径的诊断工具。
Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1, This protein initially was identified as an interacting partner for the G protein-coupled receptor kinases, and its overexpression was found to affect signaling and internalization of the prototypical beta(2)-adrenergic receptor. Here, we report that GIT1 overexpression regulates internalization of numerous, but not all, G protein-coupled receptors. The specificity of the GIT1 effect is not related to the type of C protein to which a receptor couples, but rather to the endocytic route it uses. GIT1 only affects the function of G protein-coupled receptors that are internalized through the clathrin-coated pit pathway in a beta-arrestin- and dynamin-sensitive manner. Furthermore, the GIT1 effect is not limited to G protein-coupled receptors because overexpression of this protein also affects internalization of the epidermal growth factor receptor. However, constitutive agonist-independent internalization is not regulated by GIT1, because transferrin uptake is not affected by GIT1 overexpression. Thus, GIT1 is a protein involved in regulating the function of signaling receptors internalized through the clathrin pathway and can be used as a diagnostic tool for defining the endocytic: pathway of a receptor.