Protein phosphatase-2A regulates endothelial cell motility and both the phosphorylation and the stability of focal adhesion complexes.
Solid cancers must stimulate expansion of the vascular network for continued growth. The process of angiogenesis involves endothelial cell migration so as to reorganize into vessel structures. The extent of cellular motility is regulated in part by the balance between serine/threonine kinases and protein phosphatases. In the present study, we show a decline in the activity of the serine/threonine phosphatase PP-2A in endothelial cells whose motility is stimulated by exposure to medium conditioned by either murine LLC cells or human HNSCC cells. Inhibition of endothelial cell PP-2A pharmacologically by treatment with okadaic acid also stimulated endothelial cell motility. Identification of mechanisms by which PP-2A inhibition might stimulate endothelial cell motility focused on proteins of the focal adhesions. Inhibition of PP-2A caused hyperphosphorylation of the paxillin serine residues and dephosphorylation of its tyrosine residues, dissolution of FAK/Src/paxillin complexes and decreased phosphorylation of the inhibitory Y529 residue of Src, suggesting increased Src activity. Inhibition of Src activity prevented the stimulation of PP-2A-inhibited cell motility. Our results suggest an interrelationship between tumor inhibition of PP-2A, dissolution of focal adhesion complexes and stimulated motility of endothelial cells.
Young
M Rita I
MR
Research Service, Hines Veterans Administration Hospital, Hines, IL 60141, USA. rita.young@med.va.gov
Kolesiak
Kristin
K
Meisinger
Jeremy
J
D000818:Animals; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000502:physiology
D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2