Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1.
Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1.
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DOI：
10.1016/j.cytogfr.2017.01.003
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发表时间：
2017-04
影响因子：
13
通讯作者：
Fujita M
中科院分区：
文献类型：
--
作者：
Takada Y;Takada YK;Fujita M
已经普遍接受整联蛋白细胞粘附受体参与生长因子信号传导（整联蛋白-生长因子串扰），因为整联蛋白的拮抗剂通常抑制生长因子信号传导。部分由于整合素最初被鉴定为细胞外基质（ECM）蛋白的细胞粘附受体，IGF 1和整合素之间的串扰的当前模型提出ECM配体（例如，玻连蛋白）结合整合素，IGF 1结合IGF受体1型（IGF 1 R），两个独立的信号在细胞内合并。我们的研究证明不是这样。我们发现IGF 1直接与整合素相互作用，并诱导整合素-IGF-IGF 1 R复合物在细胞表面形成。IGF 1信号传导可以在不存在ECM的情况下检测到（锚定非依赖性条件）。整联蛋白拮抗剂阻断ECM-整联蛋白相互作用和IGF-整联蛋白相互作用，并且不能区分两者。这是未检测到整合素-IGF 1相互作用的一个可能原因。有了这些新的发现，我们相信IGF-整合素的直接相互作用应该被纳入IGF 1信号转导的模型中。IGF 1的整合素结合缺陷突变体在诱导IGF信号传导方面有缺陷，尽管突变体仍然结合IGF 1 R。值得注意的是，IGF 1突变体是显性负性的，并且抑制由wt IGF 1诱导的细胞增殖，并且抑制体内肿瘤发生，因此IGF 1突变体具有作为治疗剂的潜力。
It has been generally accepted that integrin cell adhesion receptors are involved in growth factor signaling (integrin-growth factor crosstalk), since antagonists to integrins often suppress growth factor signaling. Partly because integrins have been originally identified as cell adhesion receptors to extracellular matrix (ECM) proteins, current models of the crosstalk between IGF1 and integrins propose that ECM ligands (e.g., vitronectin) bind to integrins and IGF1 binds to IGF receptor type 1 (IGF1R), and two separate signals merge inside the cells. Our research proves otherwise. We discovered that IGF1 interacts directly with integrins, and induces integrin-IGF-IGF1R complex formation on the cell surface. IGF1 signaling can be detected in the absence of ECM (anchorage-independent conditions). Integrin antagonists block both ECM-integrin interaction and IGF-integrin interaction, and do not distinguish the two. This is one possible reason why integrin-IGF1 interaction has not been detected. With these new discoveries, we believe that the direct IGF-integrin interaction should be incorporated into models of IGF1 signaling. The integrin-binding defective mutant of IGF1 is defective in inducing IGF signaling, although the mutant still binds to IGF1R. Notably, the IGF1 mutant is dominant-negative and suppresses cell proliferation induced by wt IGF1, and suppresses tumorigenesis in vivo, and thus the IGF1 mutant has potential as a therapeutic.