title: The p38/MK2/Hsp25 pathway is required for BMP-2-induced cell migration.
abstract: BACKGROUND
  Bone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K. However, the requirement of additional signaling is not clearly known.
  
  
  RESULTS
  Activation of p38 MAPK has been shown to be relevant for a number of BMP-2's physiological effects. We report here that BMP-2 regulation of cell migration and actin cytoskeleton remodelling are dependent on p38 activity. BMP-2 treatment of mesenchymal cells results in activation of the p38/MK2/Hsp25 signaling pathway downstream from the BMP receptors. Moreover, chemical inhibition of p38 signaling or genetic ablation of either p38α or MK2 blocks the ability to activate the downstream effectors of the pathway and abolishes BMP-2-induction of cell migration. These signaling effects on p38/MK2/Hsp25 do not require the activity of either Cdc42 or PAK, whereas p38/MK2 activities do not significantly modify the BMP-2-dependent activation of LIMK1, measured by either kinase activity or with an antibody raised against phospho-threonine 508 at its activation loop. Finally, phosphorylated Hsp25 colocalizes with the BMP receptor complexes in lamellipodia and overexpression of a phosphorylation mutant form of Hsp25 is able to abolish the migration of cells in response to BMP-2.
  
  
  CONCLUSIONS
  These results indicate that Cdc42/PAK/LIMK1 and p38/MK2/Hsp25 pathways, acting in parallel and modulating specific actin regulatory proteins, play a critical role in integrating responses during BMP-induced actin reorganization and cell migration.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gamell
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Susperregui
authors.forename: Ora
authors.initials: O
authors.lastname: Bernard
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rosa
authors.forename: Francesc
authors.initials: F
authors.lastname: Ventura
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D054461:Lim Kinases; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000199:Actins; D055396:Bone Morphogenetic Protein 2; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D054461:Lim Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C486113:Hsbp1 protein, mouse