title: Sprouty2 and Spred1-2 proteins inhibit the activation of the ERK pathway elicited by cyclopentenone prostanoids.
abstract: Sprouty and Spred proteins have been widely implicated in the negative regulation of the fibroblast growth factor receptor-extracellular regulated kinase (ERK) pathway. In considering the functional role of these proteins, we explored their effects on ERK activation induced by cyclopentenone prostanoids, which bind to and activate Ras proteins. We therefore found that ectopic overexpression in HeLa cells of human Sprouty2, or human Spred1 or 2, inhibits ERK1/2 and Elk-1 activation triggered by the cyclopentenone prostanoids PGA(1) and 15d-PGJ(2). Furthermore, we found that in HT cells that do not express Sprouty2 due to hypermethylation of its gene-promoter, PGA(1)-provoked ERK activation was more intense and sustained compared to other hematopoietic cell lines with unaltered Sprouty2 expression. Cyclopentenone prostanoids did not induce Sprouty2 tyrosine phosphorylation, in agreement with its incapability to activate tyrosine-kinase receptors. However, Sprouty2 Y55F, which acts as a defective mutant upon tyrosine-kinase receptor stimulation, did not inhibit cyclopentenone prostanoids-elicited ERK pathway activation. In addition, Sprouty2 did not affect the Ras-GTP levels promoted by cyclopentenone prostanoids. These results unveil both common and differential features in the activation of Ras-dependent pathways by cyclopentenone prostanoids and growth factors. Moreover, they provide the first evidence that Sprouty and Spred proteins are negative regulators of the ERK/Elk-1 pathway activation induced not only by growth-factors, but also by reactive lipidic mediators.
authors.affiliation: Unidad de Biología Celular, Área de Biología Celular y del Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain.
authors.forename: Carlota A
authors.initials: CA
authors.lastname: García-Domínguez
authors.forename: Natalia
authors.initials: N
authors.lastname: Martínez
authors.forename: Teresa
authors.initials: T
authors.lastname: Gragera
authors.forename: Andrea
authors.initials: A
authors.lastname: Pérez-Rodríguez
authors.forename: Diana
authors.initials: D
authors.lastname: Retana
authors.forename: Gonzalo
authors.initials: G
authors.lastname: León
authors.forename: Agustín
authors.initials: A
authors.lastname: Sánchez
authors.forename: José Luis
authors.initials: JL
authors.lastname: Oliva
authors.forename: Dolores
authors.initials: D
authors.lastname: Pérez-Sala
authors.forename: José M
authors.initials: JM
authors.lastname: Rojas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D011453:Prostaglandins / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003517:Cyclopentanes; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011453:Prostaglandins; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C500760:SPRED2 protein, human; C485561:SPRY2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C013905:cyclopentenone