title: Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis.
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.
authors.affiliation: Department of Biochemistry and Biophysics, Tetrad Graduate Program, University of California, San Francisco, 94131, USA.
authors.forename: Carly R K
authors.initials: CR
authors.lastname: Loeb
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015723:Gene Library; D053804:Granzymes; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000494:pharmacology*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases