TY - JOUR
T1 - The tumor suppressor WARTS activates the Omi/HtrA2-dependent pathway of cell death
AU - Kuninaka, Shinji
AU - Nomura, Masanobu
AU - Hirota, Toru
AU - Iida, Shin Ichi
AU - Hara, Toshihiro
AU - Honda, Shinobu
AU - Kunitoku, Naoko
AU - Sasayama, Takashi
AU - Arima, Yoshimi
AU - Marumoto, Tomotoshi
AU - Koja, Kageharu
AU - Yonehara, Shin
AU - Saya, Hideyuki
N1 - Funding Information:
We thank T Kitamura for the pMXpuro vector and Plat-E cells; Y Hata for the pClneoMyc APC expression plasmid; H Kuwahara for recombinant NE-dlg and PSD95 proteins; M Nakajima for helpful discussion; members of the Saya lab for valuable help and suggestions; and members of the Gene Technology Center at Kumamoto University for technical assistance. SK is a postdoctoral fellow of the Japan Society for the Promotion of Science (JSPS). This work was supported by the Research for the Future Program of the Japan Society for the promotion of Science and by a grant for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to HS).
PY - 2005/8/11
Y1 - 2005/8/11
N2 - Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine/threonine kinase and parti cipates 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.
AB - Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine/threonine kinase and parti cipates 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.
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U2 - 10.1038/sj.onc.1208682
DO - 10.1038/sj.onc.1208682
M3 - Article
C2 - 16007220
AN - SCOPUS:24044468709
SN - 0950-9232
VL - 24
SP - 5287
EP - 5298
JO - Oncogene
JF - Oncogene
IS - 34
ER -
