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International Immunology, Vol. 13, No. 10, 1265-1274, October 2001
© 2001 Japanese Society for Immunology

Nuclear localization of the tyrosine kinase Itk and interaction of its SH3 domain with karyopherin {alpha} (Rch1{alpha})

Juan J. Perez-Villar, Kathleen O'Day, Derek H. Hewgill, Steven G. Nadler and Steven B. Kanner

Immunology, Inflammation, Pulmonology and Dermatology Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA

Correspondence to: Correspondence to J. J. Perez-Villar

We report a physical and functional association between the Tec-family tyrosine kinase Itk (Emt/Tsk) and the nuclear import chaperone karyopherin {alpha} (Rch1{alpha}) in human T cells. The Itk-SH3 domain and the Rch1{alpha} proline-rich (PR) motif were crucial for the Itk/Rch1{alpha} constitutive interaction as demonstrated by directed mutagenesis of the Rch1{alpha} PR motif (proline 242 to alanine, P242A). TCR–CD3 stimulation of Jurkat T cells resulted in increased Itk/Rch1{alpha} complex formation, recruitment of karyopherin ß to the protein complex and Rch1{alpha} tyrosine phosphorylation. Analysis of in vitro kinase reactions with a panel of recombinant glutathione-S-transferase (GST) fusion tyrosine kinases (Itk, Lck, ZAP-70 and Jak3) revealed that only GST–Itk efficiently phosphorylated a recombinant GST–Rch1{alpha} fusion. We observed constitutive nuclear localization of Itk that was up-regulated following either TCR–CD3 stimulation or over-expression of wild-type Rch1{alpha} in T cells. Further, nuclear localization of Itk and TCR–CD3-mediated IL-2 production were significantly down-regulated following expression of the Rch1{alpha}-P242A mutant, implicating a role for Rch1{alpha} in the nuclear translocation of Itk.

Keywords: Itk tyrosine kinase, karyopherin {alpha}/Rch1{alpha}, , TCR-CD3, T lymphocytes, nuclear import

Transmitting editor: L. H. Glimcher


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