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Published online March 19, 2007
doi:10.1083/jcb.200607053
The Journal of Cell Biology, Vol. 176, No. 7, 1035-1047
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Primo et al.
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Article

 Essential role of PDK1 in regulating endothelial cell migration

Luca Primo1,2, Laura di Blasio1,2, Cristina Roca1,2, Sara Droetto1,2, Roberto Piva3,4, Brian Schaffhausen5, and Federico Bussolino1,2

1 Department of Oncological Sciences and 2 Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment, University of Torino, 10060 Candiolo, Italy
3 Department of Biomedical Sciences and Human Oncology and 4 Center for Experimental Research and Medical Studies, University of Turin, 10124 Turin, Italy
5 Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111

Correspondence to Luca Primo: luca.primo{at}ircc.it; or Federico Bussolino: federico.bussolino{at}ircc.it

The serine/threonine protein kinase phosphoinositide-dependent kinase 1 (PDK1) plays a central role in cellular signaling by phosphorylating members of the AGC family of kinases, including PKB/Akt. We now present evidence showing that PDK1 is essential for the motility of vascular endothelial cells (ECs) and that it is involved in the regulation of their chemotaxis. ECs differentiated from mouse embryonic stem cells lacking PDK1 completely lost their ability to migrate in vitro in response to vascular endothelial growth factor-A (VEGF-A). In addition, PDK1–/– embryoid bodies exhibit evident developmental and vascular defects that can be attributed to a reduced cell migration. Moreover, the overexpression of PDK1 increased the EC migration induced by VEGF-A. We propose a model of spatial distribution of PDK1 and Akt in which the synthesis of phosphatidylinositol 3,4,5 triphosphate at plasma membrane by activation of phosphoinositide 3-kinase recruits both proteins at the leading edge of the polarized ECs and promotes cell chemotaxis. These findings establish a mechanism for the spatial localization of PDK1 and its substrate Akt to regulate directional migration.

L. Primo and L. di Blasio contributed equally to this paper.

Abbreviations used in this paper: E, embryonic day; EB, embryoid body; EC, endothelial cell; ES, embryonic stem; MEF, murine embryonic fibroblast; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PtdIns(3,4,5)P3, phosphatidylinositol 3,4,5 triphosphate; SGK, serum- and glucocorticoid-induced protein kinase; shRNA, short hairpin RNA.


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