Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation

Nat Cell Biol. 2003 Feb;5(2):149-54. doi: 10.1038/ncb919.


SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome, a disease characterized by an inappropriate response to Epstein-Barr virus (EBV) infection. Through its SH2 domain, SAP associates with tyrosines in the cytoplasmic domain of the SLAM family of immune cell receptors, and is absolutely required for the function of these receptors. This property results from the ability of SAP to promote the selective recruitment and activation of FynT, a cytoplasmic Src-related protein tyrosine kinase (PTK). Here, we demonstrate that SAP operates in this pathway by binding to the SH3 domain of FynT, through a second region in the SAP SH2 domain distinct from the phosphotyrosine-binding motif. We demonstrate that this interaction is essential for SAP-mediated signalling in T cells, and for the capacity of SAP to modulate immune cell function. These observations characterize a biologically important signalling mechanism in which an adaptor molecule composed only of an SH2 domain links a receptor devoid of intrinsic catalytic activity to the kinase required for its function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytokines / metabolism
  • Humans
  • Immune System / physiology*
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fyn
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction / physiology*
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / metabolism
  • src Homology Domains*


  • Carrier Proteins
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • SH2D1A protein, human
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Protein-Tyrosine Kinases
  • FYN protein, human
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn