CD13/APN regulates endothelial invasion and filopodia formation.
CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide bradykinin by facilitating signal transduction at the level of the plasma membrane. Inhibition of CD13 abrogates bradykinin B(2) receptor internalization, leading to the attenuation of downstream events such as bradykinin-induced activation of Cdc42 and filopodia formation, and thus affects endothelial cell motility. Investigation into mechanisms underlying this block led us to focus on B(2)R internalization via membrane-dependent mechanisms. Membrane disruption by depletion of cholesterol or trypsinization halts B(2)R internalization, invasion, and filopodia formation, which can be recovered with addition of cholesterol. However, this functional recovery is severely impaired in the presence of CD13 antagonists, and the distribution of membrane proteins is disordered in treated cells, suggesting a role for CD13 in plasma membrane protein organization. Finally, exogenous expression of wild-type but not mutant CD13 further alters protein distribution, suggesting peptidase activity is required for CD13's regulatory activity. Therefore, CD13 functions as a novel modulator of signal transduction and cell motility via its influence on specific plasma membrane organization, thus regulating angiogenesis.
Petrovic
Nenad
N
Department of Cell Biology, Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
Schacke
Wolfgang
W
Gahagan
J Reed
JR
O'Conor
Catherine A
CA
Winnicka
Beata
B
Conway
Rebecca E
RE
Mina-Osorio
Paola
P
Shapiro
Linda H
LH
D001920:Bradykinin / Q000494:pharmacology; D018826:CD13 Antigens / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D004705:Endocytosis; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D018919:Neovascularization, Physiologic; D011554:Pseudopodia / Q000648:ultrastructure*; D043782:Receptor, Bradykinin B2 / Q000502:physiology*; D015398:Signal Transduction
D043782:Receptor, Bradykinin B2; D018826:CD13 Antigens; D001920:Bradykinin