{"doi":"10.1083/jcb.202009179","title":"Mechanism of mutant calreticulin-mediated activation of the thrombopoietin receptor in cancers","abstract":"Myeloproliferative neoplasms (MPNs) are frequently driven by mutations within the C-terminal domain (C-domain) of calreticulin (CRT). CRTDel52 and CRTIns5 are recurrent mutations. Oncogenic transformation requires both mutated CRT and the thrombopoietin receptor (Mpl), but the molecular mechanism of CRT-mediated constitutive activation of Mpl is unknown. We show that the acquired C-domain of CRTDel52 mediates both Mpl binding and disulfide-linked CRTDel52 dimerization. Cysteine mutations within the novel C-domain (C400A and C404A) and the conserved N-terminal domain (N-domain; C163A) of CRTDel52 are required to reduce disulfide-mediated dimers and multimers of CRTDel52. Based on these data and published structures of CRT oligomers, we identify an N-domain dimerization interface relevant to both WT CRT and CRTDel52. Elimination of disulfide bonds and ionic interactions at both N-domain and C-domain dimerization interfaces is required to abrogate the ability of CRTDel52 to mediate cell proliferation via Mpl. Thus, MPNs exploit a natural dimerization interface of CRT combined with C-domain gain of function to achieve cell transformation.","journal":"The Journal of Cell Biology","year":2021,"id":183341,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"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":499811,"name":"Jie Geng","orcid":"0000-0001-8722-2228","position":1,"is_corresponding":false},{"id":262026,"name":"Malathi Kandarpa","orcid":"0000-0002-0440-4964","position":2,"is_corresponding":false},{"id":584286,"name":"Sanjeeva J. Wijeyesakere","orcid":"0000-0002-4275-0438","position":3,"is_corresponding":false},{"id":584943,"name":"Ashwini Bhide","orcid":null,"position":4,"is_corresponding":false},{"id":284124,"name":"Moshe Talpaz","orcid":"0000-0003-3361-3981","position":5,"is_corresponding":false},{"id":428611,"name":"Irina D. Pogozheva","orcid":"0000-0002-3024-9574","position":6,"is_corresponding":false},{"id":292652,"name":"Malini Raghavan","orcid":"0000-0002-1345-9318","position":7,"is_corresponding":false},{"id":584285,"name":"Arunkumar Venkatesan","orcid":"0000-0002-8015-9278","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T23:48:22.008011Z","pmid":"33909030","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":[]}