Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I
Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I
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DOI：
10.1074/jbc.m313201200
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发表时间：
2004-09-03
影响因子：
4.8
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Entingh-Pearsall, A;Kahn, CR
胰岛素和胰岛素样生长因子-I（IGF-I）受体是高度同源的酪氨酸激酶受体，其在其信号传导途径中共享许多共同步骤，并且具有可以以不同亲和力结合任一受体的配体。为了精确定义胰岛素受体（IR）或IGF-I受体特异性的信号传导，我们产生了缺乏任一受体（胰岛素受体敲除（IRKO）或胰岛素样生长因子受体敲除（IGFRKO））的棕色前脂肪细胞系。对照前脂肪细胞表达的胰岛素受体少于IGF-I受体（20，000对60，000），但在分化过程中，胰岛素受体水平增加，因此成熟脂肪细胞表达的胰岛素受体略多于IGF-I受体（120，000对100，000）。在这些细胞中，胰岛素刺激IR同型二聚体磷酸化，而IGF-I激活IGF-I受体同型二聚体和杂合受体。胰岛素刺激的IRS-1磷酸化在IRKO细胞中显著受损，但在IGFRKO细胞中令人惊讶地升高。胰岛素刺激后，IRS-2磷酸化在两种细胞系中均未发生变化。在IGFRKO细胞中，IRS-1和IRS-2的IGF-I依赖性磷酸化被消除，但在IRKO细胞中未被消除。在对照细胞中，胰岛素和IGF-I均产生磷酸化Akt和MAPK的剂量依赖性增加，尽管IGF-I在同等剂量下引起更强的反应。在IRKO细胞中，磷酸化Akt的胰岛素依赖性增加在最低剂量下完全消除，并且在10 nM下仅达到对照刺激的20%。最有趣的是，对IGF-I的反应在低剂量下也受到损害，这表明胰岛素和IGF-I依赖的Akt磷酸化都需要IR。最令人惊讶的是，胰岛素或IGF-I依赖的MAPK磷酸化在任一受体缺陷细胞系中均未改变。综上所述，这些结果表明，胰岛素和IGF-I受体对胰岛素和IGF-I的共同下游组分产生不同的信号。
Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor ( insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). Control preadipocytes expressed fewer insulin receptors than IGF-I receptors ( 20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytesexpressed slightly more insulin receptors than IGF-I receptors ( 120,000 versus 100,000). In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. In IRKO cells, the insulin-dependent increase in phospho-Akt was completely abolished at the lowest dose and reached only 20% of the control stimulation at 10 nM. Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin-and IGF-I-dependent phosphorylation of Akt. Most surprisingly, insulin-or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I.