PHLDA1, another PHLDA family protein that inhibits Akt

Yu Chen, Masahiro Takikawa, Shuichi Tsutsumi, Yoko Yamaguchi, Atsushi Okabe, Mayuna Shimada, Tatsuya Kawase, Akane Sada, Issei Ezawa, Yuhei Takano, Kisaburo Nagata, Yutaka Suzuki, Kentaro Senba, Hiroyuki Aburatani, Rieko Ohki

    Research output: Contribution to journalArticle

    Abstract

    The PHLDA family (pleckstrin homology-like domain family) of genes consists of 3 members: PHLDA1, 2, and 3. Both PHLDA3 and PHLDA2 are phosphatidylinositol (PIP) binding proteins and function as repressors of Akt. They have tumor suppressive functions, mainly through Akt inhibition. Several reports suggest that PHLDA1 also has a tumor suppressive function; however, the precise molecular functions of PHLDA1 remain to be elucidated. Through a comprehensive screen for p53 target genes, we identified PHLDA1 as a novel p53 target, and we show that PHLDA1 has the ability to repress Akt in a manner similar to that of PHLDA3 and PHLDA2. PHLDA1 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 PHLDA1 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, PHLDA1 expression analysis suggests that PHLDA1 has a tumor suppressive function in breast and ovarian cancers.

    Original languageEnglish
    JournalCancer Science
    DOIs
    Publication statusAccepted/In press - 2018 Jan 1

    Fingerprint

    Phosphatidylinositols
    Proteins
    Neoplasms
    p53 Genes
    Ovarian Neoplasms
    Carrier Proteins
    Cell Membrane
    Pleckstrin Homology Domains
    Breast Neoplasms
    Genes

    Keywords

    • Akt
    • p53
    • PH domain
    • PHLDA family
    • tumor suppressor

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Chen, Y., Takikawa, M., Tsutsumi, S., Yamaguchi, Y., Okabe, A., Shimada, M., ... Ohki, R. (Accepted/In press). PHLDA1, another PHLDA family protein that inhibits Akt. Cancer Science. https://doi.org/10.1111/cas.13796

    PHLDA1, another PHLDA family protein that inhibits Akt. / Chen, Yu; Takikawa, Masahiro; Tsutsumi, Shuichi; Yamaguchi, Yoko; Okabe, Atsushi; Shimada, Mayuna; Kawase, Tatsuya; Sada, Akane; Ezawa, Issei; Takano, Yuhei; Nagata, Kisaburo; Suzuki, Yutaka; Senba, Kentaro; Aburatani, Hiroyuki; Ohki, Rieko.

    In: Cancer Science, 01.01.2018.

    Research output: Contribution to journalArticle

    Chen, Y, Takikawa, M, Tsutsumi, S, Yamaguchi, Y, Okabe, A, Shimada, M, Kawase, T, Sada, A, Ezawa, I, Takano, Y, Nagata, K, Suzuki, Y, Senba, K, Aburatani, H & Ohki, R 2018, 'PHLDA1, another PHLDA family protein that inhibits Akt', Cancer Science. https://doi.org/10.1111/cas.13796
    Chen Y, Takikawa M, Tsutsumi S, Yamaguchi Y, Okabe A, Shimada M et al. PHLDA1, another PHLDA family protein that inhibits Akt. Cancer Science. 2018 Jan 1. https://doi.org/10.1111/cas.13796
    Chen, Yu ; Takikawa, Masahiro ; Tsutsumi, Shuichi ; Yamaguchi, Yoko ; Okabe, Atsushi ; Shimada, Mayuna ; Kawase, Tatsuya ; Sada, Akane ; Ezawa, Issei ; Takano, Yuhei ; Nagata, Kisaburo ; Suzuki, Yutaka ; Senba, Kentaro ; Aburatani, Hiroyuki ; Ohki, Rieko. / PHLDA1, another PHLDA family protein that inhibits Akt. In: Cancer Science. 2018.
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