The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death.
Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi / HtrA2. Depletion of WARTS inhibited Omi / HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi / HtrA2 both in vivo and in vitro. Activation of Omi / HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.
Kuninaka
Shinji
S
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Nomura
Masanobu
M
Hirota
Toru
T
Iida
Shin-Ichi
S
Hara
Toshihiro
T
Honda
Shinobu
S
Kunitoku
Naoko
N
Sasayama
Takashi
T
Arima
Yoshimi
Y
Marumoto
Tomotoshi
T
Koja
Kageharu
K
Yonehara
Shin
S
Saya
Hideyuki
H
D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
D024101:Mitochondrial Proteins; D025521:Tumor Suppressor Proteins; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2