title: AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10.
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-X(L). 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.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Korea.
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Pyo
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Se-hoon
authors.initials: SH
authors.lastname: Hong
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Kim
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Sungmin
authors.initials: S
authors.lastname: Song
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Nam
authors.forename: Hyo Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Key-Sun
authors.initials: KS
authors.lastname: Kim
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000263:Adenylate Kinase / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053455:Caspase 10 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology / Q000502:physiology*; D009097:Multienzyme Complexes / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007527:Isoenzymes; D009097:Multienzyme Complexes; D000263:Adenylate Kinase; C110938:adenylate kinase 2; D053455:Caspase 10