Open AccessPHLDA 1, another PHLDA family protein that inhibits Akt
Author(s) -
Chen Yu,
Takikawa Masahiro,
Tsutsumi Shuichi,
Yamaguchi Yoko,
Okabe Atsushi,
Shimada Mayuna,
Kawase Tatsuya,
Sada Akane,
Ezawa Issei,
Takano Yuhei,
Nagata Kisaburo,
Suzuki Yutaka,
Semba Kentaro,
Aburatani Hiroyuki,
Ohki Rieko
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13796
Subject(s) - pleckstrin homology domain , protein kinase b , phosphatidylinositol , repressor , function (biology) , microbiology and biotechnology , akt1 , psychological repression , chemistry , gene , biology , pi3k/akt/mtor pathway , biochemistry , signal transduction , gene expression
The PHLDA family (pleckstrin homology‐like domain family) of genes consists of 3 members: PHLDA 1 , 2 , and 3 . Both PHLDA 3 and PHLDA 2 are phosphatidylinositol ( PIP ) binding proteins and function as repressors of Akt. They have tumor suppressive functions, mainly through Akt inhibition. Several reports suggest that PHLDA 1 also has a tumor suppressive function; however, the precise molecular functions of PHLDA 1 remain to be elucidated. Through a comprehensive screen for p53 target genes, we identified PHLDA 1 as a novel p53 target, and we show that PHLDA 1 has the ability to repress Akt in a manner similar to that of PHLDA 3 and PHLDA 2. PHLDA 1 has a so‐called split PH domain in which the PH domain is divided into an N‐terminal (β sheets 1‐3) and a C‐terminal (β sheets 4‐7 and an α‐helix) portions. We show that the PH domain of PHLDA 1 is responsible for its localization to the plasma membrane and binding to phosphatidylinositol. We also show that the function of the PH domain is essential for Akt repression. In addition, PHLDA 1 expression analysis suggests that PHLDA 1 has a tumor suppressive function in breast and ovarian cancers.