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J Biol Chem. 2006 Sep 22;281(38):28326-35. Epub 2006 Jun 23.

Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis.

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1
Department of Biochemistry and Biophysics, Tetrad Graduate Program, University of California, San Francisco, 94131, USA.

Abstract

Granzyme B is critical to the ability of natural killer cells and cytotoxic T lymphocytes to induce efficient cell death of virally infected or tumor cell targets. Although granzyme B can cleave and activate caspases to induce apoptosis, granzyme B can also cause caspase-independent cell death. Thirteen prospective granzyme B substrates were identified from a cDNA expression-cleavage screen, including Hsp70, Notch1, fibroblast growth factor receptor-1 (FGFR1), poly-A-binding protein, cAbl, heterogeneous nuclear ribonucleoprotein H', Br140, and intersectin-1. Validation revealed that Notch1 is a substrate of both granzyme B and caspases, whereas FGFR1 is a caspase-independent substrate of granzyme B. Proteolysis of FGFR1 in prostate cancer cells has functionally relevant consequences that indicate its cleavage may be advantageous for granzyme B to kill prostate cancer cells. Therefore, granzyme B not only activates pro-death functions within a target, but also has a previously unidentified role in inactivating pro-growth signals to cause cell death.

PMID:
16798735
DOI:
10.1074/jbc.M604544200
[Indexed for MEDLINE]
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