PubMed:19805545 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/19805545","sourcedb":"PubMed","sourceid":"19805545","source_url":"https://www.ncbi.nlm.nih.gov/pubmed/19805545","text":"Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling.\nKinase activity is known as the key biochemical property of MAPKs. Here, we report that ERK1/2 also utilizes its noncatalytic function to mediate certain signal transductions. Sustained activation of the Raf/MEK/ERK pathway induces growth arrest, accompanied by changes in cell cycle regulators (decreased retinoblastoma phosphorylation, E2F1 down-regulation, and/or p21(CIP1) up-regulation) and cell type-specific changes in morphology and expression of c-Myc or RET in the human tumor lines LNCaP, U251, and TT. Ablation of ERK1/2 by RNA interference abrogated all these effects. However, active site-disabled ERK mutants (ERK1-K71R, ERK2-K52R, and ERK2-D147A), which competitively inhibit activation of endogenous ERK1/2, could not block Raf/MEK-induced growth arrest as well as changes in the cell cycle regulators, although they effectively blocked phosphorylation of the ERK1/2 catalytic activity readouts, p90(RSK) and ELK1, as well as the cell type-specific changes. Because this indicated a potential noncatalytic ERK1/2 function, we generated stable lines of the tumor cells in which both ERK1 and ERK2 were significantly knocked down, and we further investigated the possibility using rat-derived kinase-deficient ERK mutants (ERK2-K52R and ERK2-T183A/Y185F) that were not targeted by human small hairpin RNA. Indeed, ERK2-K52R selectively restored Raf-induced growth inhibitory signaling in ERK1/2-depleted cells, as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c-Myc and morphology. However, ERK2-T183A/Y185F was less effective, indicating the requirement of TEY site phosphorylation. Our study suggests that functions of ERK1/2 other than its \"canonical\" kinase activity are also involved in the pathway-mediated growth arrest signaling.","tracks":[{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":1163,"end":1174},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0001063"},{"subj":"T1","pred":"source","obj":"CL-cell"}]},{"project":"sentences","denotations":[{"id":"T1","span":{"begin":0,"end":89},"obj":"Sentence"},{"id":"T2","span":{"begin":90,"end":156},"obj":"Sentence"},{"id":"T3","span":{"begin":157,"end":265},"obj":"Sentence"},{"id":"T4","span":{"begin":266,"end":603},"obj":"Sentence"},{"id":"T5","span":{"begin":604,"end":671},"obj":"Sentence"},{"id":"T6","span":{"begin":672,"end":1064},"obj":"Sentence"},{"id":"T7","span":{"begin":1065,"end":1410},"obj":"Sentence"},{"id":"T8","span":{"begin":1411,"end":1664},"obj":"Sentence"},{"id":"T9","span":{"begin":1665,"end":1766},"obj":"Sentence"},{"id":"T10","span":{"begin":1767,"end":1920},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"},{"subj":"T9","pred":"source","obj":"sentences"},{"subj":"T10","pred":"source","obj":"sentences"}]},{"project":"mondo_disease","denotations":[{"id":"T1","span":{"begin":396,"end":410},"obj":"Disease"},{"id":"T2","span":{"begin":571,"end":576},"obj":"Disease"},{"id":"T3","span":{"begin":1163,"end":1168},"obj":"Disease"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MONDO_0008380"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MONDO_0005070"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/MONDO_0005070"},{"subj":"T1","pred":"source","obj":"mondo_disease"},{"subj":"T2","pred":"source","obj":"mondo_disease"},{"subj":"T3","pred":"source","obj":"mondo_disease"}]},{"project":"HP-phenotype","denotations":[{"id":"T1","span":{"begin":396,"end":410},"obj":"Phenotype"},{"id":"T2","span":{"begin":571,"end":576},"obj":"Phenotype"},{"id":"T3","span":{"begin":1163,"end":1168},"obj":"Phenotype"}],"attributes":[{"id":"A1","pred":"hp_id","subj":"T1","obj":"HP:0009919"},{"id":"A2","pred":"hp_id","subj":"T2","obj":"HP:0002664"},{"id":"A3","pred":"hp_id","subj":"T3","obj":"HP:0002664"},{"subj":"T1","pred":"source","obj":"HP-phenotype"},{"subj":"T2","pred":"source","obj":"HP-phenotype"},{"subj":"T3","pred":"source","obj":"HP-phenotype"}],"namespaces":[{"prefix":"HP","uri":"http://purl.obolibrary.org/obo/HP_"}]},{"project":"NCBITAXON","denotations":[{"id":"T1","span":{"begin":565,"end":570},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":1286,"end":1289},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":1386,"end":1391},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"9606"},{"id":"A2","pred":"db_id","subj":"T2","obj":"10114"},{"id":"A3","pred":"db_id","subj":"T2","obj":"10116"},{"id":"A4","pred":"db_id","subj":"T4","obj":"9606"},{"subj":"T1","pred":"source","obj":"NCBITAXON"},{"subj":"T2","pred":"source","obj":"NCBITAXON"},{"subj":"T4","pred":"source","obj":"NCBITAXON"}]},{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":363,"end":373},"obj":"Body_part"},{"id":"T2","span":{"begin":887,"end":897},"obj":"Body_part"},{"id":"T3","span":{"begin":1603,"end":1613},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/UBERON_2000098"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_2000098"},{"id":"A3","pred":"uberon_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/UBERON_2000098"},{"subj":"T1","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T2","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T3","pred":"source","obj":"Anatomy-UBERON"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"CL-cell","color":"#ec93c3","default":true},{"id":"sentences","color":"#93deec"},{"id":"mondo_disease","color":"#ece093"},{"id":"HP-phenotype","color":"#c693ec"},{"id":"NCBITAXON","color":"#93ecac"},{"id":"Anatomy-UBERON","color":"#ec9393"}]}]}}