title: TWEAK promotes migration and invasion in MEFs through a mechanism dependent on ERKs activation and Fibulin 3 down-regulation.
abstract: TWEAK regulates multiple physio-pathological processes in fibroblasts such as fibrosis. It also induces migration and invasion in tumors and it can activate p38 MAPK in various cell types. Moreover, p38α MAPK promotes migration and invasion in several cancer cells types and in mouse embryonic fibroblasts (MEFs). However, it remains unknown if TWEAK could promote migration in fibroblasts and whether p38α MAPK might play a role. Our results reveal that TWEAK activates ERKs, Akt, and p38α/β MAPKs and reduces secreted Fibulin 3 in MEFs. TWEAK also increases migration and invasion in wt and p38α deficient MEFs, which indicates that p38α MAPK is not required to mediate these effects. In contrast, ERKs inhibition significantly decreases TWEAK-induced migration and Fibulin 3 knock-down mimics TWEAK effect. These results indicate that both ERKs activation and Fibulin 3 down-regulation would contribute to mediate TWEAK pro-migratory effect. In fact, the additional regulation of ERKs and/or p38β as a consequence of Fibulin 3 decrease might be also involved in the pro-migratory effect of TWEAK in MEFs. In conclusion, our studies uncover novel mechanisms by which TWEAK would favor tissue repair by promoting fibroblasts migration.
authors.affiliation: Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Sequera
authors.affiliation: Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vázquez-Carballo
authors.affiliation: Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Arechederra
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.|Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
authors.affiliation: Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, Universidad Complutense de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Almudena
authors.identifier: http://orcid.org/0000-0002-6495-3308
authors.initials: A
authors.lastname: Porras
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D000074049:Cytokine TWEAK / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology*; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000074049:Cytokine TWEAK; C492278:Efemp1 protein, mouse; D016326:Extracellular Matrix Proteins; C491645:Tnfsf12 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048290:Mitogen-Activated Protein Kinase 11
keywords: ERKs; Fibulin 3; TWEAK; migration