Prohibitin regulates mTOR pathway via interaction with FKBP8
- PDF / 4,335,048 Bytes
- 12 Pages / 595.276 x 785.197 pts Page_size
- 60 Downloads / 185 Views
RESEARCH ARTICLE
Prohibitin regulates mTOR pathway via interaction with FKBP8 Jiahui Zhang1, Yanan Yin1, Jiahui Wang1, Jingjing Zhang2, Hua Liu2, Weiwei Feng2, Wen Yang1, Bruce Zetter ( Yingjie Xu (
✉)1
✉)3,
1
Department of Biochemistry and Molecular and Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Obstetrics and Gynecology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 3Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2
© Higher Education Press 2020
Abstract The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K–Akt–mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an antiapoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a “switch” type regulator. We identified through immunoprecipitation–mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role. Keywords
prohibitin 1; FKBP8; mTOR; cell proliferation; cancer
Introduction The mammalian target of rapamycin (mTOR) is a major intracellular coordinator of growth and nutrient signals in eukaryotic cells. mTOR regulates several fundamental cellular processes, including the metabolism of protein, glucose, nucleotide, fatty acid, and lipid; mitochondrial biogenesis; and autophagy. As a serine–threonine protein kinase, mTOR plays a predominant role in the regulation of protein synthesis by affecting the activity of its target proteins, the translation initiation factor binding protein 4E-BP1, and the ribosomal S6 protein kinase (p70 S6 kinase) [1]. The phosphorylation of either target protein enhances protein synthesis, which results in increased cell proliferation. Therefore, the mTOR pathway is frequently activated in cancer, where the proliferation of cancer cells requires the coordination between oncogenic signaling and
Received April 24, 2020; accepted May 20, 2020 Correspondence: Yingjie Xu, [email protected]; Bruce Zetter, [email protected]
metabolic alteration [2]. For
Data Loading...
