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胰岛素受体与表皮生长因子-胰岛素受体嵌合体之间的分子间转磷酸化作用。

Intermolecular transphosphorylation between insulin receptors and EGF-insulin receptor chimerae.

作者信息

Ballotti R, Lammers R, Scimeca J C, Dull T, Schlessinger J, Ullrich A, Van Obberghen E

机构信息

INSERM U 145, Faculté de Médecine, Nice, France.

出版信息

EMBO J. 1989 Nov;8(11):3303-9. doi: 10.1002/j.1460-2075.1989.tb08491.x.

DOI:10.1002/j.1460-2075.1989.tb08491.x
PMID:2583100
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC401464/
Abstract

The insulin receptor, a glycoprotein consisting of two extracellular alpha- and two transmembrane beta-subunits, is thought to mediate hormone action by means of its tyrosine-specific protein kinase activity. To explore the mechanism of insulin receptor phosphorylation we have used NIH3T3 cells transfected with two receptor constructs: one encoding a chimeric receptor composed of the extracellular domain of the human EGF receptor and the cytosolic domain of the human insulin receptor beta-subunit, and a second construct encoding a kinase-defiecient human insulin receptor. Stimulation of these cells with EGF induced tyrosine autophosphorylation of the EGF-insulin receptor chimera (150 kd) and tyrosine phosphorylation of the beta-subunit of the kinase-deficient insulin receptor (95 kd). The phosphopeptides of the autophosphorylated cytoplasmic domain of the EGF-insulin receptor chimera were comparable to those of the transphosphorylated beta-subunit of the kinase-deficient insulin receptor and of the wild-type human insulin receptor. When immunoaffinity purified EGF-insulin receptor hybrids and kinase-deficient insulin receptors were used in a cell lysate phosphorylation assay, it was found that addition of EGF produced 32P-labeling of both receptor species. We conclude that EGF acting directly through the EGF-insulin receptor chimera causes transphosphorylation of the kinase-deficient insulin receptor. These data support the notion that autophosphorylation of the insulin receptor may proceed by an intermolecular mechanism.

摘要

胰岛素受体是一种糖蛋白，由两个细胞外α亚基和两个跨膜β亚基组成，被认为通过其酪氨酸特异性蛋白激酶活性介导激素作用。为了探究胰岛素受体磷酸化的机制，我们使用了转染了两种受体构建体的NIH3T3细胞：一种构建体编码由人表皮生长因子（EGF）受体的细胞外结构域和人胰岛素受体β亚基的胞质结构域组成的嵌合受体，另一种构建体编码激酶缺陷型人胰岛素受体。用EGF刺激这些细胞可诱导EGF-胰岛素受体嵌合体（150kd）的酪氨酸自磷酸化以及激酶缺陷型胰岛素受体β亚基（95kd）的酪氨酸磷酸化。EGF-胰岛素受体嵌合体自磷酸化胞质结构域的磷酸肽与激酶缺陷型胰岛素受体和野生型人胰岛素受体转磷酸化β亚基的磷酸肽相当。当在细胞裂解物磷酸化测定中使用免疫亲和纯化的EGF-胰岛素受体杂种和激酶缺陷型胰岛素受体时，发现添加EGF会使两种受体都产生32P标记。我们得出结论，通过EGF-胰岛素受体嵌合体直接作用的EGF会导致激酶缺陷型胰岛素受体的转磷酸化。这些数据支持胰岛素受体自磷酸化可能通过分子间机制进行的观点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/80df33c1eca2/emboj00135-0136-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/56098cf2d67e/emboj00135-0134-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/6ac5c9cf1a62/emboj00135-0135-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/c03f4cd34941/emboj00135-0135-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/e883e8f43119/emboj00135-0135-c.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/e17510cfe11c/emboj00135-0136-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/80df33c1eca2/emboj00135-0136-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/56098cf2d67e/emboj00135-0134-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/6ac5c9cf1a62/emboj00135-0135-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/c03f4cd34941/emboj00135-0135-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/e883e8f43119/emboj00135-0135-c.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/e17510cfe11c/emboj00135-0136-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f6e/401464/80df33c1eca2/emboj00135-0136-b.jpg

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Phosphorylation activates the insulin receptor tyrosine protein kinase.磷酸化作用激活胰岛素受体酪氨酸蛋白激酶。
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Tyrosine phosphorylation of the insulin receptor beta subunit activates the receptor-associated tyrosine kinase activity.胰岛素受体β亚基的酪氨酸磷酸化激活了受体相关的酪氨酸激酶活性。
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Modulating effects of the extracellular sequence of the human insulinlike growth factor I receptor on its transforming and tumorigenic potential.人胰岛素样生长因子I受体细胞外序列对其转化和致瘤潜能的调节作用。
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Diabetologia. 1994 Sep;37 Suppl 2:S125-34. doi: 10.1007/BF00400836.
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Changes in insulin-receptor tyrosine, serine and threonine phosphorylation as a result of substitution of tyrosine-1162 with phenylalanine.由于酪氨酸1162被苯丙氨酸取代导致胰岛素受体酪氨酸、丝氨酸和苏氨酸磷酸化的变化。
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Insulin receptor is an insulin-dependent tyrosine protein kinase: copurification of insulin-binding activity and protein kinase activity to homogeneity from human placenta.胰岛素受体是一种依赖胰岛素的酪氨酸蛋白激酶：从人胎盘中将胰岛素结合活性和蛋白激酶活性共纯化至同质。
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Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing.表皮生长因子受体的ATP结合位点处的点突变可消除蛋白酪氨酸激酶活性并改变细胞转运。
Cell. 1987 Oct 23;51(2):199-209. doi: 10.1016/0092-8674(87)90147-4.
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Self-phosphorylation of epidermal growth factor receptor: evidence for a model of intermolecular allosteric activation.表皮生长因子受体的自身磷酸化：分子间变构激活模型的证据
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