Cross-talk between Integrin α6β4 and Insulin-like Growth Factor-1 Receptor (IGF1R) through Direct α6β4 Binding to IGF1 and Subsequent α6β4-IGF1-IGF1R Ternary Complex Formation in Anchorage-independent Conditions
Cross-talk between Integrin α6β4 and Insulin-like Growth Factor-1 Receptor (IGF1R) through Direct α6β4 Binding to IGF1 and Subsequent α6β4-IGF1-IGF1R Ternary Complex Formation in Anchorage-independent Conditions
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DOI：
10.1074/jbc.m111.304170
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发表时间：
2012-04-06
影响因子：
4.8
通讯作者：
Takada, Yoshikazu
中科院分区：
文献类型：
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作者：
Fujita, Masaaki;Ieguchi, Katsuaki;Takada, Yoshikazu
整合素 α v beta 3 在胰岛素样生长因子 1 (IGF1) 信号传导（整合素-IGF1 受体 (IGF1R) 串扰）中发挥作用。然而，串扰的具体情况尚不清楚。在当前模型中，α v beta 3 的“配体占据”（即细胞外基质蛋白的结合）增强了 IGF1 与 IGF1R 结合诱导的信号传导。我们最近报道IGF1直接与αvβ3结合并诱导αvβ3-IGF1-IGF1R三元复合物形成。一致地，整合素结合缺陷型 IGF1 突变体 (R36E/R37E) 在诱导三元复合物形成和 IGF 信号传导方面存在缺陷，但它仍然与 IGF1R 结合。与 alpha v beta 3 一样，整合素 alpha 6 beta 4 在许多癌症中过度表达，并与癌症进展有关。在这里，我们发现α6β4直接与IGF1结合，但不与R36E/R37E结合。将对应于β 3的特异性环的β 4序列WPNSDP（残基167-172）移植到整联蛋白β 1显着增强了IGF1与β 1的结合，表明WPNSDP序列参与IGF1识别。 WT IGF1诱导α6β4-IGF1-IGF1R三元复合物形成，而R36E/R37E则不然。当细胞附着在基质上时，外源 IGF1 或 α 6 β 4 表达对细胞内信号传导影响很小或没有影响。当细胞-基质粘附减少时（在聚甲基丙烯酸2-羟乙酯包被的平板中），IGF1以α6β4依赖性方式诱导细胞内信号传导并增强细胞存活。IGF1还以α6β4依赖性方式增强软琼脂中的集落形成。这些结果表明，IGF与α6β4结合在贴壁独立条件下的IGF信号传导中起主要作用，该条件模拟体内环境，并且是一种新型的IGF信号传导途径。治疗目标。
Integrin alpha v beta 3 plays a role in insulin-like growth factor-1 (IGF1) signaling (integrin-IGF1 receptor (IGF1R) cross-talk). The specifics of the cross-talk are, however, unclear. In a current model, "ligand occupancy" of alpha v beta 3 (i.e. the binding of extracellular matrix proteins) enhances signaling induced by IGF1 binding to IGF1R. We recently reported that IGF1 directly binds to alpha v beta 3 and induces alpha v beta 3-IGF1-IGF1R ternary complex formation. Consistently, the integrin binding-defective IGF1 mutant (R36E/R37E) is defective in inducing ternary complex formation and IGF signaling, but it still binds to IGF1R. Like alpha v beta 3, integrin alpha 6 beta 4 is overexpressed in many cancers and is implicated in cancer progression. Here, we discovered that alpha 6 beta 4 directly bound to IGF1, but not to R36E/R37E. Grafting the beta 4 sequence WPNSDP (residues 167-172), which corresponds to the specificity loop of beta 3, to integrin beta 1 markedly enhanced IGF1 binding to beta 1, suggesting that the WPNSDP sequence is involved in IGF1 recognition. WT IGF1 induced alpha 6 beta 4-IGF1-IGF1R ternary complex formation, whereas R36E/R37E did not. When cells were attached to matrix, exogenous IGF1 or alpha 6 beta 4 expression had little or no effect on intracellular signaling. When cell-matrix adhesion was reduced (in poly(2-hydroxyethyl methacrylate-coated plates), IGF1 induced intracellular signaling and enhanced cell survival in an alpha 6 beta 4-dependent manner. Also IGF1 enhanced colony formation in soft agar in an alpha 6 beta 4-dependent manner. These results suggest that IGF binding to alpha 6 beta 4 plays a major role in IGF signaling in anchorage-independent conditions, which mimic the in vivo environment, and is a novel therapeutic target.