Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition

Biochem Biophys Res Commun. 2000 Mar 5;269(1):279-83. doi: 10.1006/bbrc.2000.2234.

Abstract

CTLA-4 is well documented in its negative regulation of T-cell proliferation. However, little is known regarding the signaling mechanisms induced by CTLA-4. CTLA-4 associates with the phosphatidylinositol 3-kinase, the phosphatase SHP-2 and the clathrin adaptor complexes AP-1 and AP-2. SHP-2 SH2 domain binding to CTLA-4 is unusual given the absence of a I/VxYxxI/V/L motif. Here, we demonstrate that the phosphorylation of CTLA-4 tyrosines (YVKM and YFIP) fails to allow for single or tandem SHP-2 SH2 domain binding. This was observed using wild-type and inactive SHP-2 as well as a construct with the isolated two SH2 domains. The phosphorylated YVKM and YFIP motifs therefore do not appear to represent novel binding motifs for SHP-2 SH2 domains. At the same time, we could confirm that SHP-2 can associate with CTLA-4 in murine T-cells indicating that the interaction between the phosphatase and CTLA-4 is an indirect event, possibly mediated by PI 3-kinase/SHP-2 binding.

MeSH terms

  • Abatacept
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / chemistry
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • Binding Sites / genetics
  • COS Cells
  • CTLA-4 Antigen
  • Immunoconjugates*
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tyrosine / chemistry
  • Tyrosine / metabolism
  • src Homology Domains

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Intracellular Signaling Peptides and Proteins
  • Tyrosine
  • Abatacept
  • Phosphatidylinositol 3-Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse
  • SH2 Domain-Containing Protein Tyrosine Phosphatases