Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3β- inhibitor 2-PP1 positive feedback loop

Dong Xu, Renduo Song, Guohui Wang, Prince V S Jeyabal, Amanda M. Weiskoff, Kefeng Ding, Zheng Zheng Shi

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

OLA1 is an Obg family P-loop NTPase that possesses both GTP- and ATPhydrolyzing 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.

Original languageEnglish (US)
Pages (from-to)3427-3439
Number of pages13
JournalOncotarget
Volume7
Issue number3
DOIs
StatePublished - 2016

Keywords

  • Cell signaling
  • GSK3beta
  • OLA1
  • Positive feedback loop
  • Protein phosphatase 1

ASJC Scopus subject areas

  • Oncology

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