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Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Oncogene volume 26, pages 2395–2406 (2007)Cite this article

Abstract

The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

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Abbreviations

LATS1:

large tumor-suppressor 1

HtrA:

high temperature requirement

IAP:

inhibitor of apoptosis protein

DMPK:

myotonic dystrophy protein kinase

dlg:

discs large

z-VAD-fmk:

benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone

BAF:

BOC-Asp-(OMe) fluoromethyl ketone

STS:

staurosporine

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Acknowledgements

We thank T Kitamura for supplying PLAT-E cells and pMX vector, T Yamamoto for LATS2 expression vectors and a specific antibody; Y Nishimura for L929 cells; J Moon for editorial assistance; Y Fukushima for help in preparing the manuscript; members of the Saya lab for valuable suggestions; and members of the Gene Technology Center at Kumamoto University for technical assistance. 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) and by a grant for Cancer Research from Ministry of Health, Labour and Welfare of Japan (to SK). HS is also supported by a grant from the Tokyo Biochemical Research Foundation.

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Authors and Affiliations

  1. Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    S Kuninaka, S-I Iida, T Hara, M Nomura, H Naoe, T Morisaki, M Nitta, Y Arima, T Mimori & H Saya

  2. Laboratory of Molecular and Cellular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan

    S Yonehara

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  1. S Kuninaka
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Correspondence to S Kuninaka or H Saya.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kuninaka, S., Iida, SI., Hara, T. et al. Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. Oncogene 26, 2395–2406 (2007). https://doi.org/10.1038/sj.onc.1210042

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