title: Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL.
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.
authors.affiliation: Departments of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma city, Oklahoma 73104, USA.
authors.forename: Yogita
authors.initials: Y
authors.lastname: Kanan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Hongman
authors.initials: H
authors.lastname: Song
authors.forename: Maxim
authors.initials: M
authors.lastname: Sokolov
authors.forename: Robert E
authors.initials: RE
authors.lastname: Anderson
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D009924:Organ Culture Techniques / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000401:mortality; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009687:Nuclear Proteins; D013912:Threonine; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases