{"doi":"10.1126/scisignal.ade8041","title":"Growth factor–dependent phosphorylation of Gα <sub>i</sub> shapes canonical signaling by G protein–coupled receptors","abstract":"A long-standing question in the field of signal transduction is how distinct signaling pathways interact with each other to control cell behavior. Growth factor receptors and G protein–coupled receptors (GPCRs) are the two major signaling hubs in eukaryotes. Given that the mechanisms by which they signal independently have been extensively characterized, we investigated how they may cross-talk with each other. Using linear ion trap mass spectrometry and cell-based biophysical, biochemical, and phenotypic assays, we found at least three distinct ways in which epidermal growth factor affected canonical G protein signaling by the G i -coupled GPCR CXCR4 through the phosphorylation of Gα i . Phosphomimicking mutations in two residues in the α E helix of Gα i (tyrosine-154/tyrosine-155) suppressed agonist-induced Gα i activation while promoting constitutive Gβγ signaling. Phosphomimicking mutations in the P loop (serine-44, serine-47, and threonine-48) suppressed G i activation entirely, thus completely segregating growth factor and GPCR pathways. As expected, most of the phosphorylation events appeared to affect intrinsic properties of Gα i proteins, including conformational stability, nucleotide binding, and the ability to associate with and to release Gβγ. However, one phosphomimicking mutation, targeting the carboxyl-terminal residue tyrosine-320, promoted mislocalization of Gα i from the plasma membrane, a previously uncharacterized mechanism of suppressing GPCR signaling through G protein subcellular compartmentalization. Together, these findings elucidate not only how growth factor and chemokine signals cross-talk through the phosphorylation-dependent modulation of Gα i but also how such cross-talk may generate signal diversity.","journal":"Science Signaling","year":2024,"id":446891,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"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":807708,"name":"Saptarshi Sinha","orcid":"0000-0002-4100-5727","position":1,"is_corresponding":false},{"id":1264530,"name":"Ananta James Silas","orcid":null,"position":2,"is_corresponding":false},{"id":369191,"name":"Majid Ghassemian","orcid":"0000-0003-1026-5152","position":3,"is_corresponding":false},{"id":354098,"name":"Irina Kufareva","orcid":"0000-0001-9083-7039","position":4,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":5,"is_corresponding":false},{"id":382453,"name":"Suchismita Roy","orcid":"0000-0002-6091-2357","position":0,"is_corresponding":true}],"reference_count":106,"raw_metadata":null,"created_at":"2026-07-19T02:01:54.980444Z","pmid":"38833528","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":[]}