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Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression.

Publication ,  Journal Article
Chuang, E; Alegre, ML; Duckett, CS; Noel, PJ; Vander Heiden, MG; Thompson, CB
Published in: J Immunol
July 1, 1997

CTLA-4 is a lymphocyte cell surface receptor expressed by activated T cells that functions to down-regulate T cell responses induced by TCR and CD28 stimulation. Since CTLA-4 competes with CD28 for binding to the common ligands B7-1 and B7-2, the level of CTLA-4 surface expression is likely to play an important role in its ability to inhibit CD28-dependent T cell activation. The factors that regulate these levels are poorly understood. Recent studies have revealed that following T cell activation, the majority of CTLA-4 is localized intracellularly rather than on the cell surface, and surface CTLA-4 is rapidly reinternalized. In this study, we investigate the molecular mechanism underlying the rapid clearance of CTLA-4 from the cell surface. The data demonstrate that cell surface CTLA-4 is endocytosed into clathrin-coated vesicles even in the absence of ligand. The targeting of CTLA-4 to clathrin-coated vesicles is mediated by the clathrin-associated adaptor complex AP-2. The cytoplasmic domain of CTLA-4 was found to specifically bind to AP50, the medium chain subunit of AP-2 in both yeast two-hybrid and coimmunoprecipitation assays. The interaction requires the peptide sequence 199-GVYVKM-204 in the cytoplasmic tail of CTLA-4. Mutation of the CTLA-4 amino acid residue Y201 abrogates the interaction with AP50, resulting in the accumulation of CTLA-4 at the cell surface. Together these data suggest that the interaction of CTLA-4 with AP50 plays an important role in regulating the cell surface expression of CTLA-4.

Duke Scholars

Published In

J Immunol

ISSN

0022-1767

Publication Date

July 1, 1997

Volume

159

Issue

1

Start / End Page

144 / 151

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptor Aggregation
  • Phosphoproteins
  • Nerve Tissue Proteins
  • Mutation
  • Molecular Sequence Data
  • Lymphocyte Activation
  • Jurkat Cells
  • Immunology
 

Citation

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Chuang, E., Alegre, M. L., Duckett, C. S., Noel, P. J., Vander Heiden, M. G., & Thompson, C. B. (1997). Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J Immunol, 159(1), 144–151.
Chuang, E., M. L. Alegre, C. S. Duckett, P. J. Noel, M. G. Vander Heiden, and C. B. Thompson. “Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression.J Immunol 159, no. 1 (July 1, 1997): 144–51.
Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J Immunol. 1997 Jul 1;159(1):144–51.
Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J Immunol. 1997 Jul 1;159(1):144–151.

Published In

J Immunol

ISSN

0022-1767

Publication Date

July 1, 1997

Volume

159

Issue

1

Start / End Page

144 / 151

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptor Aggregation
  • Phosphoproteins
  • Nerve Tissue Proteins
  • Mutation
  • Molecular Sequence Data
  • Lymphocyte Activation
  • Jurkat Cells
  • Immunology