SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1.
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 methyltrasnferase 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.
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115 Chicago, IL 60637, USA.|Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan.
Yuichiro
Y
Yoshioka
Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Takehiro
T
Suzuki
OncoTherapy Science, Inc., Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.
Yo
Y
Matsuo
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115 Chicago, IL 60637, USA.
Makoto
M
Nakakido
Department of Surgery, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Giichiro
G
Tsurita
Division of Medical Genetics, Department of Biomedical Science and Human Oncology (DIMO), University of Bari 'Aldo Moro', Bari 70124, Italy.
Cristiano
C
Simone
Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan.
Toshiaki
T
Watanabe
Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Naoshi
N
Dohmae
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115 Chicago, IL 60637, USA.
Yusuke
Y
Nakamura
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, MC2115 Chicago, IL 60637, USA.
Ryuji
R
Hamamoto
D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D000070539:Pleckstrin Homology Domains; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D014443:Tyrosine; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine
AKT1; PH domain; SMYD3; human cancer; lysine methylation