Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes

Mol Cell Endocrinol. 2010 Oct 26;328(1-2):70-9. doi: 10.1016/j.mce.2010.07.016. Epub 2010 Jul 21.


Podocyte injury plays an important role in the development of diabetic nephropathy. Podocytes are insulin-responsive and can develop insulin resistance, but the mechanisms are unknown. To study the role of CD2-associated protein (CD2AP) in podocyte injury, we performed a yeast two-hybrid screening on a glomerular library, and found that CD2AP bound to SH2-domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2), a negative regulator of insulin signalling. SHIP2 interacts with CD2AP in glomeruli and is expressed in podocytes, where it translocates to plasma membrane after insulin stimulation. Overexpression of SHIP2 in cultured podocytes reduces Akt activation in response to insulin, and promotes apoptosis. SHIP2 is upregulated in glomeruli of insulin resistant obese Zucker rats. These results indicate that SHIP2 downregulates insulin signalling in podocytes. The upregulation of SHIP2 in Zucker rat glomeruli prior to the age of onset of proteinuria suggests a possible role for SHIP2 in the development of podocyte injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation / genetics
  • Down-Regulation / physiology
  • Humans
  • Insulin / metabolism*
  • Kidney Glomerulus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphoric Monoester Hydrolases / physiology*
  • Podocytes / metabolism*
  • Podocytes / physiology
  • Proteinuria / genetics
  • Proteinuria / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Rats, Zucker
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Insulin
  • Phosphoric Monoester Hydrolases
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases