ROLE FOR PHOSPHATIDYLINOSITOL 3-KINASE IN THE REGULATION OF BETA-1 INTEGRIN ACTIVITY BY THE CD2 ANTIGEN

Citation
Y. Shimizu et al., ROLE FOR PHOSPHATIDYLINOSITOL 3-KINASE IN THE REGULATION OF BETA-1 INTEGRIN ACTIVITY BY THE CD2 ANTIGEN, The Journal of cell biology, 131(6), 1995, pp. 1867-1880
Citations number
83
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology
Journal title
ISSN journal
0021-9525
Volume
131
Issue
6
Year of publication
1995
Part
2
Pages
1867 - 1880
Database
ISI
SICI code
0021-9525(1995)131:6<1867:RFP3IT>2.0.ZU;2-K
Abstract
The rapid and reversible upregulation of the functional activity of in tegrin receptors on T lymphocytes is a vital step in the adhesive inte ractions that occur during successful T cell recognition of foreign an tigen and transendothelial migration. Although the ligation of several different cell surface receptors, including the antigen-specific CD3/ T cell receptor complex, the CD2, CD7, and CD28 antigens, as well as s everal chemokine receptors, has been shown to rapidly upregulate integ rin function, the intracellular signaling events that initiate this in crease in adhesion remain poorly defined. In this study, we have used DNA-mediated gene transfer to explore the role of phosphatidylinositol 3-kinase (PI 3-K) in the upregulation of beta 1 integrin functional a ctivity mediated by the CD2 antigen. CD2 was expressed in the myelomon ocytic cell line HL60, which expresses beta 1 integrins that mediate a dhesion to fibronectin and VCAM-1 in an activation-dependent manner. A ntibody stimulation of CD2 expressed on HL60 transfectants resulted wi thin minutes in increased beta 1-mediated adhesion to fibronectin and VCAM-1 at levels comparable to that obtained upon stimulation with the phorbol ester PMA. A role for PI 3-K in CD2-mediated increases in bet a 1 integrin function is suggested by: (a) the ability of the PI 3-K i nhibitor wortmannin to completely inhibit CD2-induced increases in bet a 1 integrin activity; (b) the association of PI 3-K with CD2; and (c) induced PI 3-K activity upon CD2 stimulation. The mode of association of PI 3-K with CD2 is not mediated by tyrosine phosphorylation-depend ent binding of PI 3-K via SH2 domains, since: (a) PI 3-K is associated with CD2 in unstimulated cells; (b) CD2 stimulation fails to increase the amount of associated PI 3-K; and (c) the CD2 cytoplasmic domain l acks tyrosine residues. A role for both protein kinase C and cytoskele tal rearrangements in CD2 regulation of integrin activity is also sugg ested, since a PKC inhibitor partially inhibits CD2-induced increases in beta 1 integrin function, and CD2 stimulation increases F-actin con tent in a wortmannin-sensitive manner. Analysis of human peripheral T cells indicated that CD2 stimulation also results in PI 3-K-dependent upregulation of beta 1 integrin activity. Thus, these results demonstr ate that CD2 can function as an adhesion regulator in the absence of e xpression of the CD3/T cell receptor complex; and directly implicate P I 3-K as a critical intracellular mediator involved in the regulation of beta 1 integrin functional activity by the CD2 antigen.