Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death

Min Jung Kim, Dong Gyu Jo, Gil Sun Hong, Byung Ju Kim, Michael Lai, Dong Hyung Cho, Ki Woo Kim, Arun Bandyopadhyay, Yeon Mi Hong, Do Han Kim, Chunghee Cho, Jun O. Liu, Solomon H. Snyder, Yong Keun Jung

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110 Scopus citations


Cain/cabin1 is an endogenous inhibitor of calcineurin (Cn), a calcium-dependent serine/threonine phosphatase involved in various cellular functions including apoptosis. We show here that during apoptosis cain/cabin1 is cleaved by calpain at the carboxyl terminus to generate a cleavage product with a molecular mass of 32 kDa as a necessary step leading to Cn-mediated cell death. Mouse cain/cabin1 was identified from a thymus cDNA library by an in vitro substrate-screening assay with calpain. Exposure of Jurkat cells to the calcium ionophore, A23187, induced cain/cabin1 cleavage and cell death, accompanied by activation of calpain and Cn. The calpain inhibitors, calpeptin and zLLY, suppressed both A23187-induced cain/cabin1 cleavage and Cn activation, indicating that Cn activation and cain/cabin1 cleavage are calpain-dependent. Expression of cain/cabin1 or a catalytically inactive Cn mutant [CnAβ2(1-401/H160N)] and treatment with FK506 reduced A23187-induced cell death. In vitro calpain cleavage and immuno-precipitation assays with deletion mutants of cain/cabin1 showed that cleavage occurred in the Cn-binding domain of cain/cabin1, indicating that the cleavage at its C terminus by calpain prevented cain/cabin1 from binding to Cn. In addition, in vitro binding assays showed that cain/cabin1 bound to the Cn B-binding domain of Cn A. Taken together, these results indicate that calpain cleaves the calcineurin-binding domain of cain/cabin1 to activate Cn and elicit calcium-triggered cell death.

Original languageEnglish (US)
Pages (from-to)9870-9875
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - Jul 23 2002

ASJC Scopus subject areas

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