AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10

Ho June Lee, Jong Ok Pyo, Yumin Oh, Hyo Jin Kim, Se Hoon Hong, Young Jun Jeon, Hyunjoo Kim, Dong Hyung Cho, Ha Na Woo, Sungmin Song, Jung Hyun Nam, Hyo Joon Kim, Key Sun Kim, Yong Keun Jung

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial proteins function as essential regulators in apoptosis. Here, we show that mitochondrial adenylate kinase 2 (AK2) mediates mitochondrial apoptosis through the formation of an AK2-FADD-caspase-10 (AFAC10) complex. Downregulation of AK2 attenuates etoposide- or staurosporine-induced apoptosis in human cells, but not that induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) or Fas ligand (FasL). During intrinsic apoptosis, AK2 translocates to the cytoplasm, whereas this event is diminished in Apaf-1 knockdown cells and prevented by Bcl-2 or Bcl-XL. Addition of purified AK2 protein to cell extracts first induces activation of caspase-10 via FADD and subsequently caspase-3 activation, but does not affect caspase-8. AFAC10 complexes are detected in cells undergoing intrinsic cell death and AK2 promotes the association of caspase-10 with FADD. In contrast, AFAC10 complexes are not detected in several etoposide-resistant human tumour cell lines. Taken together, these results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1303-1310
Number of pages8
JournalNature cell biology
Volume9
Issue number11
DOIs
StatePublished - Nov 2007
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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