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 dynamicall y 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 int egrin-mediated adhesion, We demonstrate in this report that the signal ing pathway that CD7 utilizes to regulate integrin activity involves t he lipid kinase phosphatidylinositol 3-kinase (Pl 3-K), CD7 stimulatio n of both jurkat T cells and resting human peripheral blood CD4(+) T c ells results in rapid association and activation of Pl 3-K with CD7, P hosphopeptide competition assays demonstrate that the association of C D7 with Pl 3-K is dependent on tyrosine phosphorylation of the SH2 bin ding motif Tyr-Clu-Asp-Met (YEDM) in the CD7 cytoplasmic domain, A rol e for Pl 3-K in the regulation of integrin function by CD7 is demonstr ated by: 1) the ability of two structurally distinct Pl 3-K inhibitors , wortmannin and LY294002, to inhibit CD7-mediated increases in beta(1 ) integrin function of human T cells; and 2) inhibition of CD7-mediate d activation of beta(1) integrin function in human T cells by expressi on of a dominant negative form of the p85 subunit of Pl 3-K, These res ults demonstrate that the CD7 Ag on human T cells is coupled to Pl 3-K and that this association is relevant to CD7-mediated signaling event s, specifically CD7-induced increases in integrin adhesiveness, Furthe rmore, these studies provide important new evidence implicating Pl 3-K in the regulation of integrin adhesiveness by multiple cell surface s ignaling receptors.