{"doi":"10.1016/j.jbc.2024.108021","title":"β1-integrin controls IGF-1R internalization and intracellular signaling","abstract":"Cell adhesion-dependent phosphorylation of insulin-like growth factor 1 receptor (IGF-1R) on its C-terminal tail (CT) at Tyr 1250/1251 promotes receptor internalization and Golgi accumulation. We previously proposed that this phosphorylation is associated with cell migration and cancer aggressiveness, distinguishing IGF-1R activity from that of insulin receptor, which lacks these tyrosines. Here, we further investigated how adhesion signaling influences IGF-1R location and activity in migratory cancer cells and R- fibroblasts. We observed that IGF-1R, in triple-negative breast cancer tissues, is predominantly intracellular and dispersed from the plasma membrane compared with nontumor tissue. Datasets from basal-like breast cancer patients indicated a strong, positive correlation between IGF-1R protein expression and that of β 1 -integrin (ITGB1). In triple-negative breast cancer cells with high ITGB1 expression, suppressing ITGB1 enhanced IGF-1R stability and its retention at the plasma membrane, and reduced IGF-1R internalization during cell adhesion. In R- fibroblasts, we observed reduced IGF-1R autophosphorylation and Golgi accumulation when ITGB1 was suppressed. The stability of a Tyr 1250/1251 Phe (FF) IGF-1R mutant was less affected by ITGB1 suppression, indicating that Tyr 1250/1251 phosphorylation is required for ITGB1-enhanced receptor internalization. Furthermore, a Tyr 1250/1251 Glu (EE) IGF-1R mutant exhibited a gain of cell migration and colony formation potential compared to WT IGF-1R or FF mutant. Tyr 1250/1251 resides within the CT 1248 SFYYS 1252 motif, which engages the IGF-1R kinase domain. In silico , we investigated how mutation of these tyrosines may alter 1248 SFYYS 1252 conformation, dictating trajectory of the distal CT. We conclude that Tyr 1250/1251 phosphorylation confers IGF-1R with unique protumorigenic signaling in a manner that is enhanced by ITGB1.","journal":"Journal of Biological Chemistry","year":2024,"id":474611,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1311531,"name":"S. O’Shea","orcid":null,"position":1,"is_corresponding":false},{"id":1311115,"name":"Leonie Rieger","orcid":"0000-0003-3263-801X","position":2,"is_corresponding":false},{"id":1311532,"name":"Órla T. Cox","orcid":null,"position":3,"is_corresponding":false},{"id":1271402,"name":"Rosemary O’Connor","orcid":"0000-0002-0687-3422","position":4,"is_corresponding":false},{"id":1311114,"name":"Niamh McDermott","orcid":"0009-0001-1827-1461","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T02:06:13.042906Z","pmid":"39608716","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}