title: Protein kinase D1 regulates VEGF-A-induced alphavbeta3 integrin trafficking and endothelial cell migration.
abstract: The bidirectional communication between integrin alphavbeta3 and vascular endothelial growth factor (VEGF) receptors acts to integrate and coordinate endothelial cell (EC) activity during angiogenesis. However, the molecular mechanisms involved in this signaling crosstalk are only partially revealed. We have found that protein kinase D1 (PKD1) was activated by VEGF-A, but not by other angiogenic factors, and associated with alphavbeta3 integrin. Moreover, knockdown of PKD1 increased endocytosis of alphavbeta3 and reduced its return from endosomes to the plasma membrane leading to accumulation of the integrin in Rab5- and Rab4-positive endosomes. Consistent with this, PKD1 knockdown caused defects in focal complex formation and reduced EC migration in response to VEGF-A. Moreover, knockdown of PKD1 reduced EC motility on vitronectin, whereas migration on collagen I was not PKD1 dependent. These results suggest that PKD1-regulated alphavbeta3 trafficking contributes to the angiogenesis process by integrating VEGF-A signaling with extracellular matrix interactions.
authors.affiliation: Institute for Cancer Research and Treatment, Candiolo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: di Blasio
authors.forename: Sara
authors.initials: S
authors.lastname: Droetto
authors.forename: Jim
authors.initials: J
authors.lastname: Norman
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D022081:Cell Surface Extensions / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D019096:Vitronectin; C089212:protein kinase D; D011493:Protein Kinase C