Regulation of IGF-1/PI3K/Akt signalling by the phosphoinositide phosphatase pharbin

J Biochem. 2011 Jul;150(1):83-93. doi: 10.1093/jb/mvr037. Epub 2011 Mar 23.

Abstract

Pharbin, a 5-phosphatase that induces arborization, is one of the phosphoinositide 5-phosphatases that is highly mutated in patients with Joubert syndrome. Pharbin can hydrolyse PI(4,5)P(2) and PI(3,4,5)P(3) and has the same substrate specificity as SHIP2 and SKIP, which negatively regulate PI3K signalling. Here, we investigated the role of pharbin in IGF-1/PI3K signalling. Ectopic expression of pharbin markedly suppressed the IGF-1-induced activation of Akt without affecting p42/44 MAP kinase phosphorylation. In contrast, pharbin silencing by RNA interference increased the IGF-1-induced phosphorylation of Akt, suggesting that pharbin negatively regulates PI3K/Akt signalling. Pharbin expression also inhibited the phosphorylation of p70 S6 kinase and 4E-BP1 as well as the subsequent protein synthesis in response to IGF-1 treatment. Taken together, these results indicate that pharbin is an important negative regulator of IGF-1/PI3K/Akt signalling and protein synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenoviridae
  • Animals
  • Cell Cycle Proteins
  • Gene Expression
  • Gene Silencing
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Insulin-Like Growth Factor I / antagonists & inhibitors*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositols / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphoproteins / metabolism
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Rats
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / genetics
  • Substrate Specificity

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • phosphoinositide-3,4,5-triphosphate
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • polyphosphoinositide phosphatase
  • Phosphoric Monoester Hydrolases
  • phosphoinositide 5-phosphatase