title: Heparan sulfate modification of the transmembrane receptor CD47 is necessary for inhibition of T cell receptor signaling by thrombospondin-1.
abstract: Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent M(r) > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium. Based on mass spectrometry, knockdown, and immunochemical analyses, the proteoglycan contains two major core proteins as follows: amyloid precursor-like protein-2 (APLP2, apparent M(r) 230,000) and CD47 (apparent M(r) > 250,000). CD47 is a known thrombospondin-1 receptor but was not previously reported to be a proteoglycan. This proteoglycan isoform of CD47 is widely expressed on vascular cells. Mutagenesis identified glycosaminoglycan modification of CD47 at Ser(64) and Ser(79). Inhibition of T cell receptor signaling by thrombospondin-1 was lost in CD47-deficient T cells that express the proteoglycan isoform of APLP2, indicating that binding to APLP2 is not sufficient. Inhibition of CD69 induction was restored in CD47-deficient cells by re-expressing CD47 or an S79A mutant but not by the S64A mutant. Therefore, inhibition of T cell receptor signaling by thrombospondin-1 is mediated by CD47 and requires its modification at Ser(64).
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20982, USA.
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Kuznetsova
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.forename: John M
authors.initials: JM
authors.lastname: Sipes
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Romeo
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Li
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D016564:Amyloid beta-Protein Precursor; D051928:CD47 Antigen / Q000378:metabolism*; D042783:Endothelial Cells; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D051928:CD47 Antigen; D006497:Heparan Sulfate; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell; D012694:Serine; D019700:Thrombospondin 1; C084104:APLP2 protein, human; C497894:CD47 protein, human