Abstract
The serine/threonine protein kinase Akt is involved in a variety of cellular processes including cell proliferation, survival, metabolism and gene expression. It is essential in vascular endothelial growth factor (VEGF)-mediated angiogenesis; however, it is not known how Akt regulates the migration of endothelial cells, a crucial process for vessel sprouting, branching and the formation of networks during angiogenesis. Here we report that Akt-mediated phosphorylation of Girdin, an actin-binding protein, promotes VEGF-dependent migration of endothelial cells and tube formation by these cells. We found that exogenously delivered adenovirus harbouring Girdin short interfering RNA in Matrigel embedded in mice, markedly inhibited VEGF-mediated angiogenesis. Targeted disruption of the Girdin gene in mice impaired vessel remodelling in the retina and angiogenesis from aortic rings, whereas Girdin was dispensable for embryonic vasculogenesis. These findings demonstrate that the Akt/Girdin signalling pathway is essential in VEGF-mediated postneonatal angiogenesis.
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Acknowledgements
We thank Y. Iwata (Ogaki Municipal Hospital) for providing haemangioma specimens, M. Nakayama (Nagoya University) for helpful discussion, and N. Takakura (Osaka University) for discussions on angiogenesis assays. This work was supported by Grants-in-Aid for 21st century Center of Excellence (COE) Research, Scientific Research (A), and Scientific Research on Priority Area 'Cancer' (to M.T.), Grant-in-Aid for Exploratory Research (to N.A.) and Program for Improvement of Research Environment for Young Researchers from Special Coordination Funds for Promoting Science and Technology (SCF) (to A.E.) commissioned by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
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To.Ki., A.E., K.M., Ta.Ka. and M.I. performed biochemical and cell biological experiments. N.A. generated Girdin-deficient mice with assistance from F.C. and analysed their phenotype. P.J. contributed to the immunohistochemistry experiments. T.W. and J.U. performed the freeze-replica electron microscopic analyses. Ta. Ko., T.M and M.T provided team leadership and project management. All authors discussed the results and commented on the manuscript.
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Kitamura, T., Asai, N., Enomoto, A. et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat Cell Biol 10, 329–337 (2008). https://doi.org/10.1038/ncb1695
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DOI: https://doi.org/10.1038/ncb1695
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