{"doi":"10.17615/p4da-5r46","title":"The HER4 Cytoplasmic Domain, But Not Its C Terminus, Inhibits Mammary Cell Proliferation","abstract":"Unlike the proliferative action of other EGF receptor family members, HER4/ErbB4 is often associated with growth inhibitory and differentiation signaling. These actions may involve HER4 two-step proteolytic processing by intra-membraneous γ-secretase, releasing the soluble, intracellular 80kDa HER4 cytoplasmic domain, s80HER4. We demonstrate that pharmacologic inhibition of either γ-secretase activity or HER4 tyrosine kinase activity blocked heregulin-dependent growth inhibition of SUM44 breast cancer cells. We next generated breast cell lines stably expressing GFP-s80HER4 (GFP fused to the N-terminus of the HER4 cytoplasmic domain, residues 676–1308), GFP-CTHER4 (GFP fused to N-terminus of the HER4 C-terminus distal to the tyrosine kinase domain, residues 989–1308) or GFP alone. Both GFP-s80HER4 and GFP-CTHER4 were found in the nucleus, but GFP-s80HER4 accumulated to a greater extent and sustained its nuclear localization. s80HER4 was constitutively tyrosine phosphorylated and treatment of cells with a specific HER family tyrosine kinase inhibitor i) blocked tyrosine phosphorylation; ii) markedly diminished GFP-s80HER4 nuclear localization, and iii) reduced STAT5A tyrosine phosphorylation and nuclear localization as well as GFP-s80HER4:STAT5A interaction. Multiple normal mammary and breast cancer cell lines, stably expressing GFP-s80HER4 (SUM44, MDA-MB-453, MCF10A, SUM102, and HC11) were growth inhibited compared to the same cell line expressing GFP-CTHER4, or GFP alone. The s80HER4-induced cell number reduction was due to slower growth, as rates of apoptosis were equivalent in GFP, GFP-CTHER4, and GFP-s80HER4 expressing cells. Lastly, GFP-s80HER4 enhanced differentiation signaling as indicated by increased basal and prolactin-dependent β–casein expression. These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition.","journal":"UNC Libraries","year":2020,"id":115226,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"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":541465,"name":"Carolyn I. Sartor","orcid":null,"position":1,"is_corresponding":false},{"id":541466,"name":"Laura S. Caskey","orcid":null,"position":2,"is_corresponding":false},{"id":541467,"name":"Rebecca S. Muraoka-Cook","orcid":null,"position":3,"is_corresponding":false},{"id":304429,"name":"H. Shelton Earp","orcid":"0000-0003-1229-4619","position":4,"is_corresponding":false},{"id":515172,"name":"Debra M. Hunter","orcid":"0000-0003-0161-5771","position":5,"is_corresponding":false},{"id":541468,"name":"Ruth Dy","orcid":null,"position":6,"is_corresponding":false},{"id":541469,"name":"Shu-Mang Feng","orcid":null,"position":7,"is_corresponding":false},{"id":541470,"name":"Xihui Yang","orcid":null,"position":8,"is_corresponding":false},{"id":453289,"name":"Hong Zhou","orcid":"0000-0002-4523-0219","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:36.820928Z","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":[]}