Figure 2.

IGF-1R trafficking routes and signaling to the mitochondria and from the Golgi and the Nucleus. (A) The IGF-1R translocates to the Golgi apparatus. In migratory cell lines, IGF-1R autophosphorylates Tyr^1250/1251 in an adhesion dependent manner. Phosphorylation of Tyr^1250/1251 IGF-1R leads to rapid IGF-1R endocytosis leads to activation of the MAPK pathway and results in translocation of the IGF-1R to the Golgi which promotes sustained SHC activation to facilitate migration. points. The release and retention of IGF-1R in the Golgi may be regulated by β1-Integrin and its interaction with the ECM. In cells with low or no migratory capacity, IGF-1R remains on the surface inducing signaling from the membrane. The interaction with other proteins, including E-cadherin, stabilizes the adhesion points and internalization rate of the IGF-1R is low. (B) IGF-1R translocates to the nucleus. IGF-1 binding to the IGF-1R induces the translocation of the membrane receptor to the nucleus. Various mechanisms have been proposed for the import of the IGF-1R to the nucleus. Nuclear IGF-1R can bind to DNA and enhance or initiate the transcription of various genes, leading to cell survival, migration, EMT and cell cycle progression. (C) IGF-1 signaling regulates mitochondrial function. The activation of the PI3-K pathway in response to IGF-1 induces the expression of the mitophagy regulators PGC1β and PRC. Inhibition of GSK-3 β by PI3-K activation leads to the release of NFE2L2/Nrf2, which translocates to the nucleus to enhance the expression of the mitophagy receptor BNIP-3. Activation of IGF1-R also enhances the expression of the UTP importer PNC-1, which was linked to cell growth and the reduction of ROS. Through these pathways IGF-1 signaling contributes to the maintenance of mitochondrial homeostasis. Figure elements adapted from Servier Medical Art (https://smart.servier.com/), under license CC-BY3.0.