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

J Biol Chem. 2006 Sep 22;281(38):28326-35. doi: 10.1074/jbc.M604544200. Epub 2006 Jun 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis*
  • Caspases / physiology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Gene Library
  • Granzymes
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Molecular Sequence Data
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, Notch1 / metabolism*
  • Serine Endopeptidases / pharmacology*


  • HSP70 Heat-Shock Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • Caspases