PHLDA1, another PHLDA family protein that inhibits Akt

• DOI: 10.1111/cas.13796
• Publication Date: 2018-09-12T05:56:52Z
• Authors: 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 Semba; Hiroyuki Aburatani; Rieko Ohki
• Keywords: Ovarian Neoplasms; 0303 health sciences; Cell Membrane; Breast Neoplasms; Original Articles; HCT116 Cells; Phosphatidylinositols; Gene Expression Regulation, Neoplastic; Alternative Splicing; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Animals; Humans; Female; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-akt; Neoplasm Transplantation; HeLa Cells; Protein Binding; Transcription Factors

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.