IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr 1250 and Tyr 1251
Menée sur des lignées de cellules cancéreuses, cette étude met en évidence un mécanisme par lequel, lors de la formation de nouvelles adhésions cellulaires, la phosphorylation des tyrosines 1250 et 1251 du récepteur IGF-1R de l'appareil de Golgi favorise la migration des cellules tumorales
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.
Science Signaling 2020