Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL

Yogita Kanan, Hiroyuki Matsumoto, Hongman Song, Maxim Sokolov, Robert E. Anderson, Raju V.S. Rajala

Research output: Contribution to journalArticle

Abstract

In our previous studies, we have shown that insulin receptor (IR) activation leads to the activation of phosphoinositide 3-kinase (PI3K) and Akt activation in rod photoreceptors. This pathway is functionally important for photoreceptor survival as deletion of IR and one of the isoforms of Akt (Akt2) resulted in stress-induced photoreceptor degeneration. However, the molecular mechanism of this degeneration is not known. Akt signaling is known to be regulated by the serine/threonine phosphatases, PH domain and leucine-rich repeat protein phosphatases (PHLPP) and PHLPP-like (PHLPPL). In this study, we characterized these two phosphatases in the retina and examined the role of IR, PI3K, and Akt signaling on the activity of PHLPP and PHLPPL. Most of the studies published on PHLPP and PHLPPL are directed toward Akt dephosphorylation; however, there are no studies available to date on how the enzyme activities of these phosphatases are regulated. We made a novel finding in this study that both PHLPP and PHLPPL activities were significantly decreased in the presence of insulin ex vivo. The insulin-induced decrease of phosphatase activities were PI3K-dependent as pre-treatment of ex vivo retinal cultures with LY294002 significantly reversed the insulin-induced inhibition. It has been shown previously that PHLPP and PHLPPL regulate the dephosphorylation of Akt isoforms, and our results demonstrate for the first time that retinal PHLPP and PHLPPL activities are under the control of the IR-activated PI3K/Akt pathway.

Original languageEnglish (US)
Pages (from-to)477-488
Number of pages12
JournalJournal of Neurochemistry
Volume113
Issue number2
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Akt isoforms
  • Cell survival
  • Insulin receptor
  • Membrane binding
  • PHLPP
  • PHLPPL

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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