c-Src mediates mitogenic signals and associates with cytoskeletal proteins upon vascular endothelial growth factor stimulation in Kaposi's sarcoma cells.
Vascular endothelial growth factor (VEGF) appears to be a critical cytokine modulating the growth and spread of Kaposi's sarcoma (KS). Furthermore, infection with the KS herpes virus results in up-regulation of VEGF and triggering of VEGF receptor activation. The molecular mechanisms regulating such cytokine-driven proliferation of KS cells are not well characterized. We investigated the role of Src-related tyrosine kinases in VEGF-mediated signaling in model KS 38 tumor cells. VEGF stimulation specifically activated c-Src kinase activity but not that of other related Src kinases such as Lyn, Fyn, or Hck in KS cells. Pyrazolopyrimidine, a selective inhibitor of Src family tyrosine kinases, significantly blocked the VEGF-induced growth of KS cells. Further studies using mutants of c-Src kinase revealed that Src mediates mitogen-activated protein kinase activation induced by VEGF. We also observed that VEGF stimulation resulted in increased tyrosine phosphorylation of the focal adhesion components paxillin and p130cas. Furthermore, VEGF induction enhanced the complex formation between Src kinase and paxillin. Src kinase appears to play an important functional role in VEGF-induced signaling in KS cells and may act to link pathways from the VEGF receptor to mitogen-activated protein kinase and cytoskeletal components, thereby effecting tumor proliferation and migration.
Munshi
N
N
Robert Mapplethorpe Laboratory, Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Groopman
J E
JE
Gill
P S
PS
Ganju
R K
RK
D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D008222:Lymphokines; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases