Activation of p38 has opposing effects on the proliferation and migration of endothelial cells.
Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.
McMullen
Meghan E
ME
Center for Cell Biology, Albany Medical College, Albany, New York 12208, USA.
Bryant
Patrick W
PW
Glembotski
Christopher C
CC
Vincent
Peter A
PA
Pumiglia
Kevin M
KM
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D018832:Molecular Chaperones; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000199:Actins; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D017874:Immediate-Early Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D005346:Fibroblast Growth Factors; C482128:MAP2K2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048669:MAP Kinase Kinase 6; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases