A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9

Biochem Biophys Res Commun. 2006 Dec 15;351(2):571-6. doi: 10.1016/j.bbrc.2006.10.079. Epub 2006 Oct 23.


Tim-3 is a member of the TIM family of proteins (T-cell immunoglobulin mucin) involved in the regulation of CD4+ T-cells. Tim-3 is a T(H)1-specific type 1 membrane protein and regulates T(H)1 proliferation and the development of tolerance. Binding of galectin-9 to the extracellular domain of Tim-3 results in apoptosis of T(H)1 cells, but the intracellular pathways involved in the regulatory function of Tim-3 are unknown. Unlike Tim-1, which is expressed in renal epithelia and cancer, Tim-3 has not been described in cells other than neuronal or T-cells. Using RT-PCR we demonstrate that Tim-3 is expressed in malignant and non-malignant epithelial tissues. We have cloned Tim-3 from an immortalized liver cell carcinoma line and identified a highly conserved tyrosine in the intracellular tail of Tim-3 (Y265). We demonstrate that Y265 is specifically phosphorylated in vivo by the interleukin inducible T cell kinase (ITK), a kinase which is located in close proximity of the TIM genes on the allergy susceptibility locus 5q33.3. Stimulation of Tim-3 by its ligand galectin-9 results in increased phosphorylation of Y265, suggesting that this tyrosine residue plays an important role in downstream signalling events regulating T-cell fate. Given the role of TIM proteins in autoimmunity and cancer, the conserved SH2 binding domain surrounding Y265 could represent a possible target site for pharmacological intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line, Tumor
  • Epithelium / metabolism
  • Galectins / physiology*
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Membrane Proteins
  • Molecular Sequence Data
  • Neoplasms / metabolism
  • Organ Specificity
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Virus / metabolism*
  • Tyrosine / metabolism*
  • src Homology Domains


  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • LGALS9 protein, human
  • Membrane Proteins
  • Receptors, Virus
  • Tyrosine
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase