{"doi":"10.1101/2021.09.29.462397","title":"PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells","abstract":"ABSTRACT Hereditary Hemorrhagic Telangiectasia (HHT) results from germline loss-of-function mutations of ENG, ACVRL1 , or SMAD4 , encoding TGFβ/BMP signaling components. Telangiectasias occur in most patients, and pulmonary, visceral, or cerebral arteriovenous malformations (AVMs) in 20-50% of these. How HHT mutations cause these clinical manifestations and why some patients suffer more serious sequelae than others is unknown. PTPN14 is a genetic modifier of pulmonary AVM incidence, and here we show by gene expression network analysis of a large panel of genetically diverse mouse lung RNA samples, that Ptpn14 is ontologically associated with markers of angiogenesis, vascular remodeling, and BMP/TGFβ and Rho kinase signaling. We demonstrate physical interaction between protein tyrosine phosphatase non-receptor, type 14 (PTPN14) and SMAD4 in nucleus and cytoplasm of primary human endothelial cells. PTPN14 suppresses ubiquitination and turnover of SMAD4 to augment tonic SMAD-mediated transcriptional readouts. This is the first report that PTPN14 binds and stabilizes SMAD4, a key component of the HHT signaling pathway. Through this mechanism, and its inhibition of YAP/TAZ signaling, PTPN14 levels may protect against development of AVMs in HHT. We discuss potential druggable targets for HHT within the ENG-ALK1-SMAD4-PTPN14 network. One Sentence Summary PTPN14 binds and stabilizes SMAD4 to potentiate BMP9 signaling in endothelial cells and components of the PTPN14 network may be drug targets for HHT.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217901,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"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":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":471768,"name":"Daniah Beleford","orcid":"0000-0003-1766-1094","position":1,"is_corresponding":false},{"id":815216,"name":"Mark A. Taylor","orcid":"0000-0001-8005-8461","position":2,"is_corresponding":false},{"id":815763,"name":"Sugandha Basu","orcid":null,"position":3,"is_corresponding":false},{"id":815217,"name":"Xinjian Cen","orcid":"0000-0002-1663-1347","position":4,"is_corresponding":false},{"id":699507,"name":"Suprita Trilok","orcid":"0000-0002-7769-0957","position":5,"is_corresponding":false},{"id":262629,"name":"Jiamin Zhang","orcid":"0000-0001-5919-002X","position":6,"is_corresponding":false},{"id":292737,"name":"Allan Balmain","orcid":"0000-0001-6549-7861","position":7,"is_corresponding":false},{"id":650063,"name":"Rosemary J. Akhurst","orcid":"0000-0002-4474-9668","position":8,"is_corresponding":false},{"id":815215,"name":"Ons Mamaï","orcid":"0000-0003-4392-0037","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:24.683898Z","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":[]}