{"doi":"10.17615/xtjy-wt37","title":"p66 shc Inhibits Insulin-like Growth Factor-I Signaling via Direct Binding to Src through Its Polyproline and Src Homology 2 Domains, Resulting in Impairment of Src Kinase Activation","abstract":"p66shc is increased in response to cell stress, and these increases regulate growth factor actions. These studies were conducted to determine how p66shc alters IGF-I-stimulated Src activation, leading to decreased IGF-I actions. Our results show that p66shc binds to Src through a polyproline sequence motif contained in the CH2 domain, a unique domain in p66shc, and IGF-I stimulates this interaction. Disruption of this interaction using a synthetic peptide containing the p66shc polyproline domain or expression of a p66shc mutant containing substitutions for the proline residues (P47A/P48A/P50A) resulted in enhanced Src kinase activity, p52shc phosphorylation, MAPK activation, and cell proliferation in response to IGF-I. To determine the mechanism of inhibition, the full-length CH2 domain and intact p66shc were tested for their ability to directly inhibit Src kinase activation in vitro. The CH2 domain peptide was clearly inhibitory, but full-length p66shc had a greater effect. Deletion of the C-terminal Src homology 2 domain in p66shc reduced its ability to inhibit Src kinase activation. These findings demonstrate that p66shc utilizes a novel mechanism for modulating Src kinase activation and that this interaction is mediated through both its collagen homologous region 2 and Src homology 2 domains.","journal":"UNC Libraries","year":2020,"id":141571,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":315243,"name":"Xinchun Shen","orcid":"0000-0002-0889-1587","position":1,"is_corresponding":false},{"id":365920,"name":"Gang Xi","orcid":"0000-0002-7020-1831","position":2,"is_corresponding":false},{"id":365923,"name":"David R. Clemmons","orcid":"0000-0001-9946-788X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:24.429854Z","pmid":null,"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":[]}