{"doi":"10.1128/mcb.14.5.2883","title":"Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.","abstract":"<jats:p>We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.</jats:p>","journal":"Molecular and Cellular Biology","year":1994,"id":636646,"datarank":0.7764224598860744,"base_score":5.176149732573829,"endowment":5.176149732573829,"self_citation_contribution":0.7764224598860744,"citation_network_contribution":0.0,"self_endowment_contribution":0.7764224598860744,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":176,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":118902,"name":"D Baltimore","orcid":null,"position":1,"is_corresponding":false},{"id":1652539,"name":"B J Mayer","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.","abstract":"<jats:p>We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.</jats:p>","is_dataset_classified":null,"base_score":5.176149732573829,"endowment":5.176149732573829,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"8164650","pmcid":null,"openalex_id":"https://openalex.org/W1956850831","authors":[],"funders":[],"total_grants":0,"fwci":9.0376,"citation_percentile":0.98531106,"influential_citations":0,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":7},{"year":2014,"count":2},{"year":2015,"count":4},{"year":2019,"count":1},{"year":2020,"count":2},{"year":2021,"count":3},{"year":2022,"count":1},{"year":2024,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/358656","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/358656","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1128/MCB.14.5.2883","host_type":"publisher"},{"url":"https://doi.org/10.1128/mcb.14.5.2883","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/8164650","host_type":"repository"},{"url":"https://resolver.caltech.edu/CaltechAUTHORS:MAYmcb94","host_type":"repository"}],"fields_of_study":["Chronic Myeloid Leukemia Treatments","Fungal Plant Pathogen Control","Eosinophilic Disorders and Syndromes"],"mesh_terms":["Animals","Base Sequence","Binding Sites","Glutathione Transferase","Humans","Kinetics","Molecular Sequence Data","Protein-Tyrosine Kinases","Proteins","Recombinant Fusion Proteins","Protein Biosynthesis","Restriction Mapping","Polymerase Chain Reaction","Mutagenesis","Genes, abl","Proto-Oncogene Proteins c-abl","Sequence Deletion","DNA Primers","GTPase-Activating Proteins","ras GTPase-Activating Proteins","Mice"],"keywords":["SH2 domain","SH3 domain","Biology","Proto-oncogene tyrosine-protein kinase Src","GRB2","HAMP domain","Adapter molecule crk","Cell biology","Tyrosine kinase","EGF-like domain","ABL","Phosphotyrosine-binding domain","Biochemistry","Phosphorylation","Signal transduction","Binding domain","Signal transducing adaptor protein","Binding site"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T17:26:35.202089Z","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":[]}