title: Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3β-inhibitor 2-PP1 positive feedback loop.
abstract: OLA1 is an Obg family P-loop NTPase that possesses both GTP- and ATP-hydrolyzing activities. Here we report that OLA1 is a GSK3β interacting protein, and through its ATPase activity, inhibits the GSK3β-mediated activation of protein serine/threonine phosphatase 1 (PP1). It is hypothesized that GSK3β phosphorylates inhibitor 2 (I-2) of PP1 at Thr-72 and activates the PP1 · I-2 complex, which in turn dephosphorylates and stimulates GSK3β, thus forming a positive feedback loop. We revealed that the positive feedback loop is normally suppressed by OLA1, and becomes over-activated under OLA1 deficiency, resulting in increased cellular PP1 activity and dephosphorylation of multiple Ser/Thr phosphoproteins, and more strikingly, decreased global protein threonine phosphorylation. Furthermore, using xenograft models of colon cancer (H116) and ovarian cancer (SKOV3), we established a correlation among downregulation of OLA1, over-activation of the positive feedback loop as indicated by under-phosphorylation of I-2, and more aggressive tumor growth. This study provides the first evidence for the existence of a GSK3β-I-2-PP1 positive feedback loop in human cancer cells, and identifies OLA1 as an endogenous suppressor of this signaling motif.
authors.affiliation: Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Renduo
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Prince V S
authors.initials: PV
authors.lastname: Jeyabal
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Weiskoff
authors.affiliation: Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Ding
authors.affiliation: Department of Translational Imaging, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000097847:Protein Phosphatase Inhibitory Proteins
chemical_list: D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D011506:Proteins; D012694:Serine; D013912:Threonine; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C522732:OLA1 protein, human
keywords: GSK3beta; OLA1; cell signaling; positive feedback loop; protein phosphatase 1