CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells
نویسندگان
چکیده
CTLA-4 is a T cell antigen that is structurally related to CD28 and serves as a high affinity ligand for the B cell antigen B7-1/2. Unlike CD28, the function of CTLA-4 is unclear, although reports have implicated the antigen in the costimulation of T cells. Recently, phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated in the costimulatory function of CD28 by virtue of its ability to bind to a pYMNM motif within the cytoplasmic tail of the antigen. In this study, we show that CTLA-4 can also associate with PI 3-kinase as detected by lipid kinase analysis and immunoblotting with anti-p85 antiserum. High pressure liquid chromatographic separation of deacylated lipids showed the presence of a peak corresponding to PI-3-P. Anti-CTLA-4 ligation of the receptor induced a significant increase in the levels of precipitable PI 3-kinase activity. Peptide binding studies revealed that the NH2- and COOH-terminal SH2 domains of p85 bind the CTLA-4 cytoplasmic pYVKM motif with an affinity (ID50: 0.6 and 0.04 microM), that is similar to CD28. CTLA-4 binding to PI 3-kinase provides further evidence that CTLA-4 is not an inert counterreceptor, but rather is coupled to an intracellular signaling molecule with the capacity to regulate cell growth.
منابع مشابه
Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.
Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed on activated T cells that can inhibit T cell responses induced by activation of the TCR and CD28. Studies with phosphorylated peptides based on the CTLA-4 intracellular domain have suggested that tyrosine phosphorylation of CTLA-4 may regulate its interactions with cytoplasmic proteins that could determin...
متن کاملCTL-associated antigen-4 ligation induces rapid T cell polarization that depends on phosphatidylinositol 3-kinase, Vav-1, Cdc42, and myosin light chain kinase.
CTLA-4 can negatively regulate cytokine production and proliferation, increase motility, and override the TCR-induced stop-signal needed for stable T cell-APC conjugation. Despite this, little is known regarding whether CTLA-4 can alter T cell morphology and the nature of the signaling events that could account for this event. In this study, we demonstrate that anti-CTLA-4 and CD3/CTLA-4 induce...
متن کاملCTLA-4 Activation of Phosphatidylinositol 3-Kinase (PI 3-K) and Protein Kinase B (PKB/AKT) Sustains T-Cell Anergy without Cell Death
The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One central question concerns the mechanism by which CTLA-4 can induce T-cell non-responsiveness without a concurrent induction of antigen induced cell death (AICD). In this study, we show that CTLA-4 activation of the p...
متن کاملO-13: Na+/K+-ATPase Alpha1 Isoform Mediates Ouabain-Induced Expression of Cyclin D1 and Proliferation of Rat Sertoli Cells
Background: Novel roles for the interaction of cardiotonic steroids to Na+/K+-ATPase have been established in recent years. The aim of the present study was to investigate the intracellular signaling events downstream the action of ouabain on Na+/K+-ATPase in Sertoli cell obtained from immature rats. Treatment of Sertoli cells with ouabain (1 μM) induced a rapid and transient increase in the ex...
متن کاملAugmentation of CTLA-4 expression by wortmannin: involvement of lysosomal sorting properties of CTLA-4.
CTLA-4 (CD152) is transiently induced on the cell surface of activated T cells and expression is limited at a low level. In this study, we investigated the possibility that phosphatidylinositol 3 kinase (PI 3-K) and other related PI kinases associated with the cytoplasmic domain of CTLA-4 are involved in intracellular trafficking and sorting of CTLA-4 protein. Treatment with micromolar concentr...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The Journal of Experimental Medicine
دوره 181 شماره
صفحات -
تاریخ انتشار 1995