Research Papers:

SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1

Yuichiro Yoshioka, Takehiro Suzuki, Yo Matsuo, Makoto Nakakido, Giichiro Tsurita, Cristiano Simone, Toshiaki Watanabe, Naoshi Dohmae, Yusuke Nakamura and Ryuji Hamamoto _

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Oncotarget. 2016; 7:75023-75037. https://doi.org/10.18632/oncotarget.11898

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Yuichiro Yoshioka1,6, Takehiro Suzuki2, Yo Matsuo3, Makoto Nakakido1, Giichiro Tsurita4, Cristiano Simone5, Toshiaki Watanabe6, Naoshi Dohmae2, Yusuke Nakamura1, Ryuji Hamamoto1

1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115 Chicago, IL 60637, USA

2Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan

3OncoTherapy Science, Inc., Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan

4Department of Surgery, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

5Division of Medical Genetics, Department of Biomedical Science and Human Oncology (DIMO), University of Bari ‘Aldo Moro’, Bari 70124, Italy

6Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan

Correspondence to:

Ryuji Hamamoto, email: rhamamoto@medicine.bsd.uchicago.edu

Keywords: SMYD3, AKT1, lysine methylation, PH domain, human cancer

Received: April 08, 2016     Accepted: August 24, 2016     Published: September 08, 2016


AKT1 is a cytosolic serine/threonine kinase that is overexpressed in various types of cancer and has a central role in human tumorigenesis. Although it is known that AKT1 is post-translationally modified in various ways including phosphorylation and ubiquitination, methylation has not been reported so far. Here we demonstrate that the protein lysine methyltransferase SMYD3 methylates lysine 14 in the PH domain of AKT1 both in vitro and in vivo. Lysine 14-substituted AKT1 shows significantly lower levels of phosphorylation at threonine 308 than wild-type AKT1, and knockdown of SMYD3 as well as treatment with a SMYD3 inhibitor significantly attenuates this phosphorylation in cancer cells. Furthermore, substitution of lysine 14 diminishes the plasma membrane accumulation of AKT1, and cancer cells overexpressing lysine 14-substiuted AKT1 shows lower growth rate than those overexpressing wild-type AKT1. These results imply that SMYD3-mediated methylation of AKT1 at lysine 14 is essential for AKT1 activation and that SMYD3-mediated AKT1 methylation appears to be a good target for development of anti-cancer therapy.

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