Research ArticleCell Biology

IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251

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Science Signaling  26 May 2020:
Vol. 13, Issue 633, eaba3176
DOI: 10.1126/scisignal.aba3176

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How IGF-1R promotes cell migration

Signaling through the insulin-like growth factor 1 receptor (IGF-1R) promotes cancer progression, but therapies that limit IGF-1R signaling have performed poorly. Rieger et al. found that the residues Tyr1250 and Tyr1251, which are required for IGF-1R to support cancer cell growth (see the Focus by Crudden and Girnita), underwent autophosphorylation when cells were adherent. Experiments with IGF-1Rs containing phosphomimetic or nonphosphorylatable substitutions at these sites demonstrated that IGF-1 induced IGF-1R translocation to the Golgi, where it enhanced cell migration before being degraded or recycled to the plasma membrane. These findings show that phosphorylation-dependent trafficking of IGF-1R promotes aggressive cancer cell behaviors and may explain why targeting plasma membrane–localized IGF-1R is not effective.


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 (Tyr1250/1251) 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 Tyr1250/1251 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.

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