Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.
Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.
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DOI：
10.1371/journal.pone.0027488
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Forbes BE
中科院分区：
文献类型：
--
作者：
Alvino CL;Ong SC;McNeil KA;Delaine C;Booker GW;Wallace JC;Forbes BE
胰岛素样生长因子- ii （IGF-II）促进细胞增殖和存活，在胎儿正常发育和胎盘功能中起重要作用。IGF-II高亲和力结合胰岛素样生长因子受体（IGF-1R）和胰岛素受体异构体A （IR-A）。有趣的是，IGF-II和IR-A在癌症中经常上调，IGF-II通过这两种受体促进癌症增殖。配体诱导胰岛素（IR）和IGF-1R活化的机制尚不清楚。最近解决的红外结构揭示了一个折叠的二聚体，每个受体一半上的残基产生两个潜在的配体结合袋。位点定向诱变已经将对配体结合很重要的受体残基映射到配体结合袋内的两个单独的位点上，我们最近表明，igf有两个单独的结合表面，它们与受体位点1和2相互作用。在这项研究中，我们描述了一系列通过突变IGF-II的Glu12产生的部分IGF-1R和IR激动剂。通过比较受体结合亲和力、诱导负协同性的能力和受体激活的能力，我们提供了证据，表明残基Glu12在两个受体之间架起桥梁，导致受体激活。这项研究为IGF-II受体结合和激活的机制提供了新的见解，这可能对未来开发其治疗癌症的抑制剂具有重要意义。
Insulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2. In this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation. This study provides novel insight into the mechanism of receptor binding and activation by IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer.
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影响因子：
4.1
作者：
FRANCIS, GL;APLIN, SE;WALLACE, JC
通讯作者：
WALLACE, JC
影响因子：
64.8
作者：
McKern, Neil M.;Lawrence, Michael C.;Ward, Colin W.
通讯作者：
Ward, Colin W.
影响因子：
8.2
作者：
DEMEYTS, P
通讯作者：
DEMEYTS, P
影响因子：
4.8
作者：
Delaine, Carlie;Alvino, Clair L.;Forbes, Briony E.
通讯作者：
Forbes, Briony E.
影响因子：
3.5
作者：
KING, R;WELLS, JRE;FRANCIS, GL
通讯作者：
FRANCIS, GL