A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9.
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.[1]References
- A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. van de Weyer, P.S., Muehlfeit, M., Klose, C., Bonventre, J.V., Walz, G., Kuehn, E.W. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
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