The N terminus of mannose 6-phosphate/insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration.
Leukocyte migration to sites of inflammation is a multistep process involving transient adhesion to the endothelium followed by cell surface-controlled proteolysis for transmigration through the vessel wall and chemotactic movement within tissues. One of the key players in this machinery appears to be the urokinase-type plasminogen activator (uPA)/uPA receptor system. The role of uPA and its receptor (CD87) in plasminogen (Plg) activation, cell adhesion, and chemotaxis is well established; however, less is known of how these activities are regulated. Here we provide evidence that the mannose 6-phosphate/insulin-like growth factor 2 receptor (CD222) controls CD87-mediated functions. Expression of human CD222 in CD222-/- mouse fibroblasts down-regulated Plg activation, cell adhesion, and chemotaxis induced by the uPA/CD87 system. In addition, we demonstrate that the N-terminal region of CD222, which is similar to the Plg-binding site of streptokinase, plays a crucial role in binding of CD87 and Plg. A peptide derived from this region in CD222 is able to disrupt the physical interaction of CD222 with CD87 and, furthermore, mimics the inhibitory effects of CD222 on CD87 functions. Taken together, our results indicate a novel role for CD222 in regulation of fibrinolysis, cell adhesion, and migration.
Institute of Immunology, Vienna International Research Cooperation Center at Novartis Forschungs-institut, University of Vienna, Vienna A-1235, Austria.
Vladimír
V
Leksa
Samuel
S
Godár
Marek
M
Cebecauer
Ivan
I
Hilgert
Johannes
J
Breuss
Ulrich H
UH
Weidle
Václav
V
Horejsí
Bernd R
BR
Binder
Hannes
H
Stockinger
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D017931:DNA Primers; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D017386:Sequence Homology, Amino Acid; D013300:Streptokinase / Q000737:chemistry / Q000378:metabolism
D017931:DNA Primers; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D013300:Streptokinase