Insulin receptor function in fibroblasts from patients with leprechaunism. Differential alterations in binding, autophosphorylation, kinase activity, and receptor-mediated internalization.
Insulin receptor function in fibroblasts from patients with leprechaunism. Differential alterations in binding, autophosphorylation, kinase activity, and receptor-mediated internalization.
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小妖精患者成纤维细胞中胰岛素受体的功能。
DOI：
10.1172/jci113739
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Kahn,CR
中科院分区：
文献类型：
--
作者：
Reddy,SS;Lauris,V;Kahn,CR
对3例罕见的严重胰岛素抵抗和新生儿生长迟缓的精灵症患者(Ark-1、Minn-1和CaN-1)的皮肤成纤维细胞的胰岛素受体功能进行了检测。所有三个患者细胞系的胰岛素结合率都低于对照组的15%。这主要是由于CaN-1中受体的亲和力降低，以及另外两个细胞系(Ark-1和Minn-1)中受体数量的减少。当表达为总结合胰岛素的一小部分时，细胞相关胰岛素内化和降解的百分比在患者细胞系和对照组之间没有差异。然而，氯喹对对照细胞的降解抑制了50%，对来自患者的细胞没有影响。当胰岛素结合正常化时，胰岛素受体自动磷酸化在CaN-1细胞中是正常的，但在Ark-1和Minn-1细胞中减少。相反，在所有三种患者细胞系中，受体相关酪氨酸激酶对外源底物的活性都降低了。这些结果表明，小妖精是一种生化异质性疾病，与受体功能的各种变化有关。来自Ark-1和Minn-1的细胞在受体自磷酸化和激酶活性方面表现出平行的变化。来自CAN-1的细胞表现出正常的受体自动磷酸化，但降低了激酶活性，从而显示出一种独特的突变胰岛素受体。尽管激酶活性降低，但所有三种细胞株都表现出正常的胰岛素内化速率，但减少了溶酶体介导的降解。我们的数据表明，受体的自磷酸化和激酶活性可能分别受到调节，而激酶活性可能与胰岛素降解有关，但不一定与内化有关。
Insulin receptor function was examined in cultured skin fibroblasts from three patients with leprechaunism (Ark-1, Minn-1, and Can-1), a rare syndrome of severe insulin resistance and neonatal growth retardation. All three patients cell lines demonstrated insulin binding less than 15% of control. This was primarily due to reduced affinity of the receptor in Can-1 and due to reduced number of receptors in the other two cell lines (Ark-1 and Minn-1). When expressed as a fraction of total insulin bound, the percentage of cell-associated insulin internalized and degraded did not differ between the patient cell lines and the controls. However, chloroquine, which inhibited degradation by 50% in the control cells, had no effect in the cells from the patients. When normalized to insulin binding, insulin receptor autophosphorylation was normal in cells from Can-1, but reduced in those of Ark-1 and Minn-1. In contrast, the receptor-associated tyrosine kinase activity toward exogenous substrates was decreased in all three patient cell lines. These results suggest that leprechaunism is a biochemically heterogenous disease associated with a variety of alterations in receptor function. Cells from Ark-1 and Minn-1 exhibit parallel alterations in receptor autophosphorylation and kinase activity. Cells from Can-1 demonstrate normal receptor autophosphorylation but reduced kinase activity, thus displaying a unique form of a mutant insulin receptor. Despite reduced kinase activity, all three cell lines exhibit normal rates of insulin internalization, but decreased lysosomal-mediated degradation. Our data imply that receptor autophosphorylation and kinase activity may be regulated separately and that kinase activity may be linked to insulin degradation, but not necessarily internalization.Images