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  • The EMBO Journal (2005) 24, 3532 - 3542
  • doi:10.1038/sj.emboj.7600827

Published online: 29 September 2005

Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8

Soonah Shin1, Yoonmi Lee1, Wooseok Kim1, Hyeonseok Ko1, Hyeyeon Choi1 and Kunhong Kim1,2,3

  1. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science of Yonsei University, Seodaemun-gu, Seoul, Korea
  2. Nanomedical National Core Research Center, Pohang, Korea
  3. PNI Inc., Ltd, Pohang, Korea

Correspondence to:

Kunhong Kim, Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea. Tel.: +822 228 1680; Fax: +822 312 5041; E-mail: kimkh34@yumc.yonsei.ac.kr

Received 8 April 2005; Accepted 5 September 2005

Although caspase-2 is believed to be involved in death receptor-mediated apoptosis, the exact function, mode of activation, and regulation of caspase-2 remain unknown. Here we show that protein kinase (PK) CK2 phosphorylates procaspase-2 directly at serine-157. When intracellular PKCK2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner. The activated caspase-2 then processes procaspase-8 monomers between the large and small subunits, thereby priming cancer cells for TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The processed procaspase-8 that is recruited to death-inducing signaling complex by TRAIL engagement becomes fully activated, and cancer cells undergo apoptosis. PKCK2 activity is low in TRAIL-sensitive cancer cell lines but high in TRAIL-resistant cancer cell lines. Thus, downregulating PKCK2 activity is required for TRAIL-mediated apoptosis to occur in TRAIL-resistant cancer cells. Our data provide novel insights into the regulation, mode of activation, and function of caspase-2 in TRAIL-mediated apoptosis.

  • Keywords:

    • caspase-2,
    • caspase-8,
    • PKCK2,
    • priming,
    • TRAIL