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首页> 外文期刊>Frontiers in Endocrinology >Ligand-Binding Affinity at the Insulin Receptor Isoform-A and Subsequent IR-A Tyrosine Phosphorylation Kinetics are Important Determinants of Mitogenic Biological Outcomes
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Ligand-Binding Affinity at the Insulin Receptor Isoform-A and Subsequent IR-A Tyrosine Phosphorylation Kinetics are Important Determinants of Mitogenic Biological Outcomes

机译：胰岛素受体同工型-A的配体结合亲和力和随后的IR-A酪氨酸磷酸化动力学是有丝分裂生物学结果的重要决定因素。

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The insulin receptor (IR) is a tyrosine kinase receptor that can mediate both metabolic and mitogenic biological actions. The IR isoform-A (IR-A) arises from alternative splicing of exon 11 and has different ligand binding and signaling properties compared to the IR isoform-B. The IR-A not only binds insulin but also insulin-like growth factor-II (IGF-II) with high affinity. IGF-II acting through the IR-A promotes cancer cell proliferation, survival, and migration by activating some unique signaling molecules compared to those activated by insulin. This observation led us to investigate whether the different IR-A signaling outcomes in response to IGF-II and insulin could be attributed to phosphorylation of a different subset of IR-A tyrosine residues or to the phosphorylation kinetics. We correlated IR-A phosphorylation to activation of molecules involved in mitogenic and metabolic signaling (MAPK and Akt) and receptor internalization rates (related to mitogenic signaling). We also extended this study to incorporate two ligands that are known to promote predominantly mitogenic [(His~(4), Tyr~(15), Thr~(49), Ile~(51)) IGF-I, qIGF-I] or metabolic (S597 peptide) biological actions, to see if common mechanisms can be used to define mitogenic or metabolic signaling through the IR-A. The threefold lower mitogenic action of IGF-II compared to insulin was associated with a decreased potency in activation of Y960, Y1146, Y1150, Y1151, Y1316, and Y1322, in MAPK phosphorylation and in IR-A internalization. With the poorly mitogenic S597 peptide, it was a decreased rate of tyrosine phosphorylation rather than potency that was associated with a low mitogenic potential. We conclude that both decreased affinity of IR-A binding and kinetics of IR-A phosphorylation can independently lead to a lower mitogenic activity. None of the studied parameters could account for the lower metabolic activity of qIGF-I.
机译：胰岛素受体（IR）是一种酪氨酸激酶受体，可以介导代谢和促有丝分裂的生物学作用。 IR同工型-A（IR-A）源自外显子11的选择性剪接，并且与IR同工型-B相比具有不同的配体结合和信号传导性质。 IR-A不仅以高亲和力结合胰岛素，而且还结合胰岛素样生长因子-II（IGF-II）。与胰岛素激活的信号分子相比，通过IR-A起作用的IGF-II通过激活一些独特的信号分子来促进癌细胞的增殖，存活和迁移。该观察结果使我们研究了响应IGF-II和胰岛素的不同IR-A信号转导结果是否可归因于IR-A酪氨酸残基的不同子集的磷酸化或磷酸化动力学。我们将IR-A磷酸化与参与有丝分裂和代谢信号传导（MAPK和Akt）和受体内在化速率（与有丝分裂信号传导有关）的分子的激活相关。我们还扩展了这项研究，纳入了两个已知主要促进促有丝分裂的配体[（His〜（4），Tyr〜（15），Thr〜（49），Ile〜（51））IGF-1，qIGF-1。或代谢（S597肽）生物学作用，以查看是否可以使用常见机制来定义通过IR-A的促有丝分裂或代谢信号传导。与胰岛素相比，IGF-II的有丝分裂作用降低了三倍，与在MAPK磷酸化和IR-A内在化过程中激活Y960，Y1146，Y1150，Y1151，Y1316和Y1322的效力降低有关。有丝分裂原力较弱的S597肽，是酪氨酸磷酸化率降低，而不是有力的，这与低有丝分裂原电位有关。我们得出结论，IR-A结合亲和力下降和IR-A磷酸化动力学都可以独立导致更低的促有丝分裂活性。所研究的参数均不能解释qIGF-1的较低代谢活性。

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