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Vascular endothelial growth factor-mediated activation of p38 is dependent upon Src and RAFTK/Pyk2

Oncogene volume 23, pages 1275–1282 (2004)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) induces activation of p38 mitogen-activated protein kinase (MAPK) in primary endothelial cells and may be critical for VEGF-induced angiogenesis. We investigated the molecular basis for p38 activation in response to VEGF. The expression of a C-terminal splice variant of FAK, FRNK, had no affect on VEGF-induced activation of p38; however, expression of a dominant-negative RAFTK/Pyk2 mutant led to a decrease in the activation of p38, but had no affect on extracellular signal-regulated kinase (ERK). Since calcium regulates RAFTK/Pyk2, we investigated its role in p38 activity. Preincubation with EGTA suppressed p38 activation, while calcium ionophore induced p38 activity. Inhibition of phospholipase C (PLC) resulted in complete inhibition of ERK, while having no affect on p38 activity. These data suggested a bifurcation in the regulation of MAPKs that occurs at the level of PLC and RAFTK/Pyk2 activation. Src family kinases interact with RAFTK/Pyk2. Inhibition of Src by either pharmacological or genetic means decreased p38 activity. Finally, we found that both Src and RAFTK/Pyk2 were essential for endothelial cell migration. These data identified a novel regulatory network involving extracellular calcium, RAFTK/Pyk2, Src and p38. This signaling network appears to be critical for VEGF-induced endothelial cell migration.

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Acknowledgements

We thank Drs Allen Hall, Gary Bokoch, Roger Davis and Hava Avraham for providing cDNAs. We also thank Drs Michael Dipersio, Peter Vincent and Allison Berrier for critical reading of the manuscript. In addition, we acknowledge the support of Developmental Therapeutics Program of the National Cancer Institute for providing VEGF and endothelial cells. This work was supported by Public Health Service Grants R01-CA-81419 from the National Cancer Institute (KP) and an institutional predoctoral training grant (T32-HL-07194).

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  1. Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA

    Meghan McMullen & Kevin Pumiglia

  2. Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA

    Rebecca Keller

  3. Division of Cardiology, Cinncinnati Children's Hospital, Cinncinnati, OH, USA

    Mark Sussman

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  1. Meghan McMullen
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Correspondence to Kevin Pumiglia.

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McMullen, M., Keller, R., Sussman, M. et al. Vascular endothelial growth factor-mediated activation of p38 is dependent upon Src and RAFTK/Pyk2. Oncogene 23, 1275–1282 (2004). https://doi.org/10.1038/sj.onc.1207243

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