IL-2 INDUCES BETA(2)-INTEGRIN ADHESION VIA A WORTMANNIN LY294002-SENSITIVE, RAPAMYCIN-RESISTANT PATHWAY - PHOSPHORYLATION OF A 125-KILODALTON PROTEIN CORRELATES WITH INDUCTION OF ADHESION, BUT NOT MITOGENESIS/

Besides its function as a growth factor, IL-2 induces beta(2)-integrin -dependent, homotypic adhesion of IL-2R-positive T cells, In this stud y, we investigated how IL-2R are functionally and biochemically linked to the beta(2)-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta(2)-integrin-dependent, homotypic adhesion i n Ag-specific, human T cell lines, The IL-2 adhesion response is block ed by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (P I-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-in duced proliferation without inhibiting IL-2-induced adhesion. Herbimyc in A and genestein, inhibitors of protein tyrosine kinases, inhibit cy tokine-induced adhesion and mitogenesis in parallel, whereas cytochala sin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mit ogenesis, IL-2R ligation rapidly (<5 min) induces tyrosine phosphoryla tion of several proteins, the most prominent being signal transducer a nd activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125), Wortma nnin, LY294002, and cytochalasin E almost completely inhibit cytokine- induced tyrosine phosphorylation of p125, whereas tyrosine phosphoryla tion of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins i s unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125, Taken together, these data suggest that 1) I L-2R ligation induces homotypic adhesion through a wortmannin/LY294002 -sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a cr itical role in cytokine-induced adhesion, and 3) adhesion, but not mit ogenesis, correlates with enhanced tyrosine phosphorylation of an as y et unidentified protein of 125 kDa.