Inhibition of SH2-domain containing inositol phosphatase 2 (SHIP2) in insulin producing INS1E cells improves insulin signal transduction and induces proliferation.
Inhibition of the lipid phosphatase SH2-domain containing inositol phosphatase 2 (SHIP2) in L6-C10 muscle cells, in 3T3-L1 adipocytes and in the liver of db/db mice has been shown to ameliorate insulin signal transduction and established SHIP2 as a negative regulator of insulin action. Here we show that SHIP2 inhibition in INS1E insulinoma cells increased Akt, glycogen synthase kinase 3 and extracellular signal-regulated kinases 1 and 2 phosphorylation. SHIP2 inhibition did not prevent palmitate-induced apoptosis, but increased cell proliferation. Our data raise the interesting possibility that SHIP2 inhibition exerts proliferative effects in beta-cells and further support the attractiveness of a specific inhibition of SHIP2 for the treatment of type 2 diabetes.
Grempler
Rolf
R
Department of Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397 Biberach an der Riss, Germany. rolfgrempler@yahoo.de
Leicht
Stefanie
S
Kischel
Ivonne
I
Eickelmann
Peter
P
Redemann
Norbert
N
D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007340:Insulinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D019925:Cyclin A; D007328:Insulin; D050505:Mutant Proteins; D012333:RNA, Messenger; D019308:Palmitic Acid; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases