Title |
c-ABL modulates MAP kinases activation downstream of VEGFR-2 signaling by direct phosphorylation of the adaptor proteins GRB2 and NCK1
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Published in |
Angiogenesis, February 2012
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DOI | 10.1007/s10456-012-9252-6 |
Pubmed ID | |
Authors |
Francesca Anselmi, Maurizio Orlandini, Marina Rocchigiani, Caterina De Clemente, Ahmad Salameh, Claudia Lentucci, Salvatore Oliviero, Federico Galvagni |
Abstract |
Vascular Endothelial Growth Factor-A (VEGF-A) is a key molecule in normal and tumor angiogenesis. This study addresses the role of c-ABL as a novel downstream target of VEGF-A in primary Human Umbilical Vein Endothelial Cells (HUVEC). On the basis of immunoprecipitation experiments, in vitro kinase assay and RNA interference, we demonstrate that VEGF-A induces the c-ABL kinase activity through the VEGF Receptor-2/Phosphatidylinositol-3-Kinase pathway. By treating HUVEC with the specific tyrosine kinase inhibitor STI571 and over-expressing a dominant negative c-ABL mutant, we show that the VEGF-A-activated c-ABL reduces the amplitude of Mitogen-Activated Protein Kinases (ERK1/2, JNKs and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins NCK1 and GRB2 mutants we further show that the negative loop on p38 is mediated by c-ABL phosphorylation at tyrosine 105 of the adaptor protein NCK1, while the phosphorylation at tyrosine 209 of GRB2 down-modulates ERK1/2 and JNKs signaling. These findings suggest that c-ABL function is to establish a correct and tightly controlled response of endothelial cells to VEGF-A during the angiogenic process. |
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Demographic breakdown
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Mendeley readers
Geographical breakdown
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Demographic breakdown
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Student > Bachelor | 7 | 18% |
Researcher | 6 | 16% |
Student > Master | 4 | 11% |
Other | 2 | 5% |
Other | 4 | 11% |
Unknown | 6 | 16% |
Readers by discipline | Count | As % |
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Computer Science | 2 | 5% |
Engineering | 2 | 5% |
Other | 4 | 11% |
Unknown | 5 | 13% |