A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.
Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1beta, and transforming growth factor-beta. Cellular migration was blocked by SB203580, an inhibitor of p38(MAPK). Time course experiments demonstrated increased phosphorylation of p38(MAPK). Activation of p38(MAPK) resulted in the phosphorylation of HSP27 (heat shock protein 27), which may modulate F-actin polymerization. Inhibition of p38(MAPK) activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38(MAPK), increased cell migration, whereas overexpression of p38alpha MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38(MAPK) pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.
Hedges
J C
JC
Cell and Molecular Biology Program, University of Nevada at Reno, Reno, Nevada 89557-0046, USA.
Dechert
M A
MA
Yamboliev
I A
IA
Martin
J L
JL
Hickey
E
E
Weber
L A
LA
Gerthoffer
W T
WT
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002465:Cell Movement; D004285:Dogs; D005260:Female; D006360:Heat-Shock Proteins / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009130:Muscle, Smooth / Q000166:cytology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D006360:Heat-Shock Proteins; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases