Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr¹²⁵⁰ and Tyr¹²⁵¹ (Tyr^1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1–induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr^1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface.

尽管胰岛素样生长因子 1 (IGF-1) 信号促进肿瘤生长和癌症进展，但针对 IGF-1 受体 (IGF-1R) 的疗法显示出较差的临床疗效。为了解决癌细胞中 IGF-1R 的活性以及它与密切相关的胰岛素受体 (IR) 的活性有何不同，我们专注于 IGF-1R C 末端尾部的两种酪氨酸，它们不存在于 IR 中，并且对于IGF-1 介导的癌细胞存活、迁移和致瘤性生长。我们发现 Tyr ¹²⁵⁰和 Tyr ¹²⁵¹ (Tyr ^1250/1251) 以细胞粘附依赖性方式自磷酸化。为了研究这种磷酸化的后果，我们生成了 IGF-1R 的拟磷酸化 Y1250E/Y1251E (EE) 和非磷酸化 Y1250F/Y1251F (FF) 突变形式。尽管在激酶活性和信号传导方面完全胜任，但 EE 突变体比野生型或 FF 受体更快地内化和降解。IGF-1 促进野生型和 EE IGF-1R 在高尔基体中的积累，而 FF 突变体保留在质膜上。高尔基体相关 IGF-1R 信号传导是迁移性癌细胞的一个特征，高尔基体破坏会损害 IGF-1 诱导的信号传导和细胞迁移。在形成新的细胞粘附后，IGF-1R 从高尔基体瞬时重新定位到质膜上。因此，Tyr ^{1250/1251 的}磷酸化促进 IGF-1R 易位到高尔基体并从高尔基体发出信号以支持侵袭性癌症表型。这一过程将 IGF-1R 与 IR 信号区分开来，并且可能导致靶向细胞表面 IGF-1R 的抗体临床疗效不佳。