{"doi":"10.1016/j.cell.2021.03.031","title":"Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules","abstract":"Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.","journal":"Cell","year":2021,"id":146869,"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":190,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"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":624148,"name":"Juan Guan","orcid":"0000-0002-5944-6512","position":1,"is_corresponding":false},{"id":624149,"name":"Dana S. Neel","orcid":"0000-0002-1788-4784","position":2,"is_corresponding":false},{"id":625021,"name":"Hannah R. Allegakoen","orcid":null,"position":3,"is_corresponding":false},{"id":625022,"name":"Yone Phar Lin","orcid":null,"position":4,"is_corresponding":false},{"id":411732,"name":"David T. Brown","orcid":"0000-0001-7531-8230","position":5,"is_corresponding":false},{"id":355492,"name":"Yu‐Ting Chou","orcid":"0000-0001-8524-4220","position":6,"is_corresponding":false},{"id":625023,"name":"Ann Heslin","orcid":null,"position":7,"is_corresponding":false},{"id":576854,"name":"Nilanjana Chatterjee","orcid":"0000-0002-1203-5222","position":8,"is_corresponding":false},{"id":624150,"name":"Shriya Perati","orcid":"0000-0002-7797-0959","position":9,"is_corresponding":false},{"id":624151,"name":"Shruti Menon","orcid":"0009-0002-8392-0728","position":10,"is_corresponding":false},{"id":624152,"name":"Tan Nguyen","orcid":"0000-0003-2696-9170","position":11,"is_corresponding":false},{"id":311105,"name":"Jayanta Debnath","orcid":"0000-0002-8745-4069","position":12,"is_corresponding":false},{"id":624153,"name":"Alejandro Ramirez","orcid":"0000-0002-8803-8630","position":13,"is_corresponding":false},{"id":564556,"name":"Xiaoyu Shi","orcid":"0000-0002-9634-2659","position":14,"is_corresponding":false},{"id":245880,"name":"Bin Yang","orcid":"0000-0001-5138-4663","position":15,"is_corresponding":false},{"id":495633,"name":"Siyu Feng","orcid":"0000-0001-8499-6914","position":16,"is_corresponding":false},{"id":585995,"name":"Suraj Makhija","orcid":"0000-0002-2490-2434","position":17,"is_corresponding":false},{"id":406504,"name":"Bo Huang","orcid":"0000-0003-1704-4141","position":18,"is_corresponding":false},{"id":3224,"name":"Trever G. Bivona","orcid":"0000-0001-5734-4128","position":19,"is_corresponding":false},{"id":624147,"name":"Asmin Tulpule","orcid":"0000-0002-3507-7476","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T23:42:24.567796Z","pmid":"33848463","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":[]}