title: CEACAM1: a key regulator of vascular permeability.
abstract: Carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is an immunoglobulin-like cell surface co-receptor expressed on epithelial, hematopoietic and endothelial cells. CEACAM1 functions as an adhesion molecule, mainly binding to itself or other members of the CEA family. We and others have previously shown that CEACAM1 is crucial for in vivo vascular integrity during ischemic neo-vascularization. Here, we have deciphered the roles of CEACAM1 in normal and pathological vascularization. We have found that Ceacam1-/- mice exhibit a significant increase in basal vascular permeability related to increased basal Akt and endothelial nitric oxide synthase (eNOS) activation in primary murine lung endothelial cells (MLECs). Moreover, CEACAM1 deletion in MLECs inhibits VEGF-mediated nitric oxide (NO) production, consistent with defective VEGF-dependent in vivo permeability in Ceacam1-/- mice. In addition, Ceacam1-null mice exhibit increased permeability of tumor vasculature. Finally, we demonstrate that CEACAM1 is tyrosine-phosphorylated upon VEGF treatment in a SHP-1- and Src-dependent manner, and that the key residues of the long cytoplasmic domain of CEACAM1 are crucial for CEACAM1 phosphorylation and NO production. This data represents the first report, to our knowledge, of a functional link between CEACAM1 and the VEGFR2/Akt/eNOS-mediated vascular permeability pathway.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Nouvion
authors.forename: Malika
authors.initials: M
authors.lastname: Oubaha
authors.forename: Sarah
authors.initials: S
authors.lastname: Leblanc
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Holger
authors.initials: H
authors.lastname: Jastrow
authors.forename: Robert
authors.initials: R
authors.lastname: Kammerer
authors.forename: Valérie
authors.initials: V
authors.lastname: Breton
authors.forename: Claire
authors.initials: C
authors.lastname: Turbide
authors.forename: Suleyman
authors.initials: S
authors.lastname: Ergun
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gratton
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008168:Lung / Q000166:cytology; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D019000:Phosphotyrosine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse