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Published online
doi:10.1083/jcb.200708200
The Journal of Cell Biology, Vol. 179, No. 5, 923-934
The Rockefeller University Press, 0021-9525 $30.00
© deSouza et al.
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Article

A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation



Nikhil deSouza1, Jie Cui1, Miroslav Dura1, Thomas V. McDonald2,3, and Andrew R. Marks1

1 Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032
2 Department of Medicine and 3 Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY 10461

Correspondence to A.R. Marks: arm42{at}columbia.edu

Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation.

Abbreviations used in this paper: BCR, B cell receptor; [Ca2+]i, intracellular Ca2+; CRAC, Ca2+ release–activated Ca2+; HEK, human embryonic kidney; IL-2, interleukin-2; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; LAT, linker of activated T cells; NFAT, nuclear factor of activated T cells; PM, plasma membrane; STIM1, stromal interaction molecule 1; TCR, T cell receptor; TK, thymidine kinase; WT, wild type.


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