{"doi":"10.1073/pnas.0510651103","title":"Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein","abstract":"<jats:p>\n                    The Ras → Raf → MEK1/2 → extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway couples mitogenic signals to cell proliferation. B-Raf and Raf-1 function within an oligomer wherein they are regulated in part by mutual transactivation. The MAPK kinase kinase (MAP3K) mixed-lineage kinase 3 (MLK3) is required for mitogen activation of B-Raf and cell proliferation. Here we show that the kinase activity of MLK3 is not required for support of B-Raf activation. Instead, MLK3 is a component of the B-Raf/Raf-1 complex and is required for maintenance of the integrity of this complex. We show that the activation of ERK and the proliferation of human schwannoma cells bearing a loss-of-function mutation in the\n                    <jats:italic>neurofibromatosis 2</jats:italic>\n                    (\n                    <jats:italic>NF2</jats:italic>\n                    ) gene require MLK3. We find that merlin, the product of\n                    <jats:italic>NF2</jats:italic>\n                    , blunts the activation of both ERK and c-Jun N-terminal kinase (JNK). Finally, we demonstrate that merlin and MLK3 can interact\n                    <jats:italic>in situ</jats:italic>\n                    and that merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. Thus, MLK3 is part of a multiprotein complex and is required for ERK activation. The levels of this complex may be negatively regulated by merlin.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2006,"id":689010,"datarank":0.6862066467755076,"base_score":4.574710978503383,"endowment":4.574710978503383,"self_citation_contribution":0.6862066467755076,"citation_network_contribution":0.0,"self_endowment_contribution":0.6862066467755076,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":96,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1800024,"name":"Dazhong Xu","orcid":null,"position":1,"is_corresponding":false},{"id":1586329,"name":"Gene Hung","orcid":null,"position":2,"is_corresponding":false},{"id":809756,"name":"Ali Andalibi","orcid":null,"position":3,"is_corresponding":false},{"id":1800025,"name":"David J. Lim","orcid":null,"position":4,"is_corresponding":false},{"id":1800026,"name":"Zhijun Luo","orcid":null,"position":5,"is_corresponding":false},{"id":295596,"name":"David H. Gutmann","orcid":"0000-0002-3127-5045","position":6,"is_corresponding":false},{"id":1710647,"name":"John M. Kyriakis","orcid":null,"position":7,"is_corresponding":false},{"id":1710646,"name":"Deborah N. Chadee","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein","abstract":"<jats:p>\n                    The Ras → Raf → MEK1/2 → extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway couples mitogenic signals to cell proliferation. B-Raf and Raf-1 function within an oligomer wherein they are regulated in part by mutual transactivation. The MAPK kinase kinase (MAP3K) mixed-lineage kinase 3 (MLK3) is required for mitogen activation of B-Raf and cell proliferation. Here we show that the kinase activity of MLK3 is not required for support of B-Raf activation. Instead, MLK3 is a component of the B-Raf/Raf-1 complex and is required for maintenance of the integrity of this complex. We show that the activation of ERK and the proliferation of human schwannoma cells bearing a loss-of-function mutation in the\n                    <jats:italic>neurofibromatosis 2</jats:italic>\n                    (\n                    <jats:italic>NF2</jats:italic>\n                    ) gene require MLK3. We find that merlin, the product of\n                    <jats:italic>NF2</jats:italic>\n                    , blunts the activation of both ERK and c-Jun N-terminal kinase (JNK). Finally, we demonstrate that merlin and MLK3 can interact\n                    <jats:italic>in situ</jats:italic>\n                    and that merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. Thus, MLK3 is part of a multiprotein complex and is required for ERK activation. The levels of this complex may be negatively regulated by merlin.\n                  </jats:p>","is_dataset_classified":null,"base_score":4.574710978503383,"endowment":4.574710978503383,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"16537381","pmcid":"PMC1450194","openalex_id":"https://openalex.org/W2105024940","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"R01 CA112399","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM 46577","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA 112399","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM046577","title":null}],"total_grants":4,"fwci":4.1933,"citation_percentile":0.94872523,"influential_citations":0,"citation_trend":[{"year":2012,"count":8},{"year":2013,"count":8},{"year":2014,"count":8},{"year":2015,"count":1},{"year":2016,"count":2},{"year":2017,"count":2},{"year":2018,"count":1},{"year":2019,"count":2},{"year":2020,"count":3},{"year":2021,"count":2},{"year":2022,"count":3},{"year":2023,"count":2},{"year":2024,"count":3},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"http://doi.org/10.1073/pnas.0510651103","host_type":"repository"},{"url":"http://doi.org/10.1073/pnas.0510651103","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.0510651103","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.0510651103","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/16537381","host_type":"repository"}],"fields_of_study":["Melanoma and MAPK Pathways","Neurofibromatosis and Schwannoma Cases","Cellular Mechanics and Interactions","Animals","Enzyme Activation","Extracellular Signal-Regulated MAP Kinases","Humans","MAP Kinase Kinase Kinases","Multienzyme Complexes","Mutation","Neurofibromin 2","Proto-Oncogene Proteins B-raf","Proto-Oncogene Proteins c-raf","Rats","Tumor Suppressor Proteins","Mitogen-Activated Protein Kinase Kinase Kinase 11"],"mesh_terms":["Mitogen-Activated Protein Kinase Kinase Kinase 11","Animals","Enzyme Activation","Humans","Multienzyme Complexes","Mutation","Proto-Oncogene Proteins c-raf","MAP Kinase Kinase Kinases","Tumor Suppressor Proteins","Neurofibromin 2","Extracellular Signal-Regulated MAP Kinases","Proto-Oncogene Proteins B-raf","Rats"],"keywords":["MAP kinase kinase kinase","Mitogen-activated protein kinase kinase","Cyclin-dependent kinase 9","Cyclin-dependent kinase 4","MAP2K7","c-Raf","Cyclin-dependent kinase 2","ASK1","Cell biology","Biology","MAPK/ERK pathway","Protein kinase A","Kinase","Protein kinase R","Merlin (protein)","Cancer research","Chemistry","Biochemistry","Suppressor","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-19T21:21:05.283301Z","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":[]}