Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active -arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1R activated the basal arr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of arr2. The models of arr2/IGF-1R and arr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants arr2 and arr2 further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1R and the RING domain of MEX3A. The truncated-arr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of arr2/IGF-1R and arr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1R promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372823PMC
http://dx.doi.org/10.1016/j.apsb.2023.04.001DOI Listing

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