{"doi":"10.1101/2024.05.30.596653","title":"Nanoclustering and signaling of KRAS G12C and KRAS G12D respond to lipid acyl chain remodeling in an allele-specific manner","abstract":"Abstract Small GTPase KRAS mutated at hotspots, such as G12, G13 and Q61, are major drivers of cancer and display allele-specific oncogenic properties, which are not well understood. KRAS mutants require precise spatiotemporal distribution to the proteolipid nanoclusters on the plasma membrane (PM) for efficient signaling. We recently reported allele-specific lipid sensing of KRAS mutants. KRAS G12D , KRAS G12V and KRAS Q61H favor the unsaturated phosphatidylserine (PS), while KRAS G12C and KRAS G13D gain enrichment of the saturated PS, cholesterol and/or phosphoinositol 4,5-bisphosphate (PIP 2 ). We, here, examined how the allele-specific lipid sensing of KRAS mutants contributes to their allele-specific signaling and activities. We now show that the stable expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) elevates the saturated phospholipids and reduces the mixed-chain lipids, especially PS species. Our super-resolution electron microscopy (EM)–spatial analysis revealed that the LPCAT1 expression perturbs the PM nanoclustering of KRAS G12D , without affecting that of KRAS G12C . LPCAT1 suppresses the KRAS-dependent mitogen-activated protein kinases (MAPKs) signaling and the MAPK-regulated proliferation and colony formation of the KRAS G12D -expressing human pancreatic PANC1 cells, while promoting those of the KRAS G12C -expressing MiaPaCa-2 cells. Mouse embryonic fibroblasts (MEF) transformed with KRAS G12C contain more saturated lipids than those expressing KRAS G12D . Concordantly, patient tumor genomics analysis illustrated that expression of LPCAT1 and KRAS mutants negatively correlate in pancreatic adenocarcinoma with KRAS G12D as a dominant driver, but loses correlation in lung adenocarcinoma with KRAS G12C as a major driver. Thus, the allele-specific lipid sensing of KRAS mutants contributes to their pathological activities.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488561,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":302569,"name":"Liang Hong","orcid":"0000-0003-1101-7046","position":1,"is_corresponding":false},{"id":1333550,"name":"Walaa Kattan","orcid":null,"position":2,"is_corresponding":false},{"id":666440,"name":"Haoqiang Ying","orcid":"0000-0002-0172-7530","position":3,"is_corresponding":false},{"id":309159,"name":"Haoqiang Ying","orcid":"0000-0003-0616-2310","position":4,"is_corresponding":false},{"id":1167531,"name":"Junchen Liu","orcid":"0000-0003-2765-9780","position":5,"is_corresponding":false},{"id":302566,"name":"Yong Zhou","orcid":"0000-0002-0214-8151","position":6,"is_corresponding":false},{"id":992384,"name":"Neha Arora","orcid":"0000-0001-9198-8744","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:19.655720Z","pmid":"38853864","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":[]}