CD7-mediated regulation of integrin adhesiveness on human T cells involves tyrosine phosphorylation-dependent activation of phosphatidylinositol 3-kinase.
The functional activity of integrin receptors on T cells is dynamically regulated so that T cells can alternate rapidly between adhesive and nonadhesive states. The CD7 Ag is one of several molecules on T cells that can transduce intracellular signals that rapidly up-regulate integrin-mediated adhesion. We demonstrate in this report that the signaling pathway that CD7 utilizes to regulate integrin activity involves the lipid kinase phosphatidylinositol 3-kinase (PI 3-K). CD7 stimulation of both Jurkat T cells and resting human peripheral blood CD4+ T cells results in rapid association and activation of PI 3-K with CD7. Phosphopeptide competition assays demonstrate that the association of CD7 with PI 3-K is dependent on tyrosine phosphorylation of the SH2 binding motif Tyr-Glu-Asp-Met (YEDM) in the CD7 cytoplasmic domain. A role for PI 3-K in the regulation of integrin function by CD7 is demonstrated by: 1) the ability of two structurally distinct PI 3-K inhibitors, wortmannin and LY294002, to inhibit CD7-mediated increases in beta1 integrin function of human T cells; and 2) inhibition of CD7-mediated activation of beta3 integrin function in human T cells by expression of a dominant negative form of the p85 subunit of PI 3-K. These results demonstrate that the CD7 Ag on human T cells is coupled to PI 3-K and that this association is relevant to CD7-mediated signaling events, specifically CD7-induced increases in integrin adhesiveness. Furthermore, these studies provide important new evidence implicating PI 3-K in the regulation of integrin adhesiveness by multiple cell surface signaling receptors.
Chan
A S
AS
Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor 48109, USA.
Mobley
J L
JL
Fields
G B
GB
Shimizu
Y
Y
D019011:Antigens, CD7 / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000276:immunology*; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism
D019011:Antigens, CD7; D016023:Integrins; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)