AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10.
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.
Lee
Ho-June
HJ
Department of Life Science, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Korea.
Pyo
Jong-Ok
JO
Oh
Yumin
Y
Kim
Hyo-Jin
HJ
Hong
Se-hoon
SH
Jeon
Young-Jun
YJ
Kim
Hyunjoo
H
Cho
Dong-Hyung
DH
Woo
Ha-Na
HN
Song
Sungmin
S
Nam
Jung-Hyun
JH
Kim
Hyo Joon
HJ
Kim
Key-Sun
KS
Jung
Yong-Keun
YK
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
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