The small subunit of calpain, a calcium-dependent cysteine protease, was found to interact with the cytoplasmic domain of the common cytokine receptor gamma chain (gammac) in a yeast two-hybrid interaction trap assay. This interaction was functional as demonstrated by the ability of calpain to cleave in vitro-translated wild-type gammac, but not gammac containing a mutation in the PEST (proline, glutamate, serine, and threonine) sequence in its cytoplasmic domain, as well as by the ability of endogenous calpain to mediate cleavage of gammac in a calcium-dependent fashion. In T cell receptor-stimulated murine thymocytes, calpain inhibitors decreased cleavage of gammac. Moreover, in single positive CD4(+) thymocytes, not only did a calpain inhibitor augment CD3-induced proliferation, but antibodies to gammac blocked this effect. Finally, treatment of cells with ionomycin could inhibit interleukin 2-induced STAT protein activation, but this inhibition could be reversed by calpain inhibitors. Together, these data suggest that calpain-mediated cleavage of gammac represents a mechanism by which gammac-dependent signaling can be controlled.
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| http://dx.doi.org/10.1073/pnas.94.21.11534 | DOI Listing |
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