title: Shear stress-dependent downregulation of the adhesion-G protein-coupled receptor CD97 on circulating leukocytes upon contact with its ligand CD55.
abstract: Adhesion G protein-coupled receptors (aGPCRs) are two-subunit molecules, consisting of an adhesive extracellular α subunit that couples noncovalently to a seven-transmembrane β subunit. The cooperation between the two subunits and the effect of endogenous ligands on the functioning of aGPCRs is poorly understood. In this study, we investigated the interaction between the pan-leukocyte aGPCR CD97 and its ligand CD55. We found that leukocytes from CD55-deficient mice express significantly increased levels of cell surface CD97 that normalized after transfer into wild-type mice because of contact with CD55 on both leukocytes and stromal cells. Downregulation of both CD97 subunits occurred within minutes after first contact with CD55 in vivo, which correlated with an increase in plasma levels of soluble CD97. In vitro, downregulation of CD97 on CD55-deficient leukocytes cocultured with wild-type blood cells was strictly dependent on shear stress. In vivo, CD55-mediated downregulation of CD97 required an intact circulation and was not observed on cells that lack contact with the blood stream, such as microglia. Notably, de novo ligation of CD97 did not activate signaling molecules constitutively engaged by CD97 in cancer cells, such as ERK and protein kinase B/Akt. We conclude that CD55 downregulates CD97 surface expression on circulating leukocytes by a process that requires physical forces, but based on current evidence does not induce receptor signaling. This regulation can restrict CD97-CD55-mediated cell adhesion to tissue sites.
authors: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors: Olga N
authors: ON
authors: Karpus
authors: Henrike
authors: H
authors: Veninga
authors: Robert M
authors: RM
authors: Hoek
authors: Dennis
authors: D
authors: Flierman
authors: Jaap D
authors: JD
authors: van Buul
authors: Corianne C
authors: CC
authors: Vandenakker
authors: Ed
authors: E
authors: vanBavel
authors: M Edward
authors: ME
authors: Medof
authors: René A W
authors: RA
authors: van Lier
authors: Kris A
authors: KA
authors: Reedquist
authors: Jörg
authors: J
authors: Hamann
mesh_terms: D000818:Animals; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: C490633:Adgre5 protein, mouse; D018958:CD55 Antigens; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases