CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway.
Cell migration is critical for many processes, such as angiogenesis, inflammation, development and wound healing, and is also involved in tumour progression and metastasis. Here we show that CXCL12, complement factor 5a (C5a), hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF)-BB, which stimulate cell migration, also activate p38alpha MAPK. Pharmacological inhibition of this protein kinase with SB 203580 or BIRB 0796, or the genetic ablation of p38alpha MAPK, blocked cell migration induced by the aforementioned chemo-attractants. Macrophages from mice lacking one or more of the other p38 MAPK isoforms showed normal cell migration in response to C5a. We also show that the activation of p38alpha MAPK in response to CXCL12 requires the p21-activated protein kinases (PAK)-1 and PAK-2. MAPKAP-K2 is a protein kinase that is activated by p38alpha MAPK. Reducing its expression using RNA interference blocked CXCL12-induced HeLa cell migration, while macrophages from mice that do not express MAPKAP-K2 failed to migrate in response to C5a. Moreover, RNA interference against the small heat shock protein 27 (HSP27), a physiological substrate of MAPKAP-K2, blocked the CXCL12-induced cell migration. These results demonstrate a general and essential role of the PAK-p38alpha MAPK-MAPKAP-K2-HSP27 signalling pathway in mediating the effects of chemotactic stimuli on cell migration.
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, CIR building, Dow Street, Dundee DD1 5EH, United Kingdom. s.rousseau@dundee.ac.uk
Simon
S
Rousseau
Ignacio
I
Dolado
Victoria
V
Beardmore
Natalia
N
Shpiro
Rudolfo
R
Marquez
Angel R
AR
Nebreda
J Simon C
JS
Arthur
Lauren M
LM
Case
Marc
M
Tessier-Lavigne
Matthias
M
Gaestel
Ana
A
Cuenda
Philip
P
Cohen
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054462:p21-Activated Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015936:Complement C5a; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D048308:Mitogen-Activated Protein Kinase 14; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C515256:Cxcl12 protein, mouse; C486699:Hspb2 protein, mouse; C515905:Pak1 protein, mouse; C515909:Pak2 protein, mouse