Activation of the Lck tyrosine protein kinase by the herpesvirus saimiri Tip protein involves two binding interactions

David A. Hartley, Kambiz Amdjadi, Tamara R. Hurley, Troy C. Lund, Peter G. Medveczky, Bartholomew M. Sefton

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The Tip protein of Herpesvirus saimiri strain 484C binds to and activates the Lck tyrosine protein kinase. Two sequences in the Tip protein were previously shown to be involved in binding to Lck. A proline-rich region, residues 132-141, binds to the SH3 domain of the Lck protein. We show here that the other Lck-binding domain, residues 104-113, binds to the carboxyl-terminal half of Lck and that this binding does not require the Lck SH3 domain. Mutated Tip containing only one functional Lck-binding domain can bind stably to Lck, although not as strongly as wild-type Tip. Interaction of Tip with Lck through either Lck-binding domain increases the activity of Lck in vivo. Simultaneous binding of both domains is required for maximal activation of Lck. The transient expression of Tip in T cells was found to stimulate both Stat3-dependent and NF-AT-dependent transcription. Mutant forms of Tip lacking one or the other of the two Lck-binding domains retained the ability to stimulate Stat3-dependent transcription. Tip lacking the proline-rich Lck-binding domain exhibited almost wild-type activity in this assay. In contrast, ablation of either Lck-binding domain abolished the ability of Tip to stimulate NF-AT-dependent transcription. Full biological activity of Tip, therefore, appears to require both Lck-binding domains. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)339-348
Number of pages10
JournalVirology
Volume276
Issue number2
DOIs
StatePublished - Oct 25 2000

Bibliographical note

Funding Information:
We thank Joseph Lin for help with the preparation of the anti-Tip antiserum, Richard Jove and Christopher Herold for reagents, Jack Bui for reagents and advice, and Robbie Schulte and Gary Chiang for critical reading of the manuscript. D. Hartley was supported by training Grant T32-CA09523 from the National Cancer Institute of the National Institutes of Health and fellowship PF-4483 from the American Cancer Society. The study was supported by Grants CA14195, CA42350, and CA43264 from the National Cancer Institute of the National Institutes of Health.

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