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


ABSTRACT: 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.

SUBMITTER: Yoshioka Y 

PROVIDER: S-EPMC5342720 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Yoshioka Yuichiro Y   Suzuki Takehiro T   Matsuo Yo Y   Nakakido Makoto M   Tsurita Giichiro G   Simone Cristiano C   Watanabe Toshiaki T   Dohmae Naoshi N   Nakamura Yusuke Y   Hamamoto Ryuji R  

Oncotarget 20161101 46


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 lowe  ...[more]

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