Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation

• Published in: The EMBO journal 2003-08, Vol.22 (16), p.4178-4189
• Main Authors: Falasca, Marco, Maffucci, Tania, Brancaccio, Anna, Piccolo, Enza, Stein, Robert C
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Androstadienes - pharmacology; Animals; Cell Line; Chromones - pharmacology; Deoxyglucose - pharmacokinetics; EMBO20; EMBO37; Enzyme Inhibitors - pharmacology; Glucose Transporter Type 4; GLUT4; Hypoglycemic Agents - pharmacology; insulin; Insulin - pharmacology; Membrane Microdomains - metabolism; Membranes; Mice; Monosaccharide Transport Proteins - metabolism; Morpholines - pharmacology; Muscle Proteins; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - antagonists & inhibitors; Phosphatidylinositol Phosphates - biosynthesis; Phosphatidylinositol Phosphates - pharmacology; phosphatidylinositol-3-phosphate; Platelet-Derived Growth Factor - pharmacology; Recombinant Fusion Proteins - metabolism; rho GTP-Binding Proteins - metabolism; Second Messenger Systems; TC10; Translocation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdg402

Phosphatidylinositol‐3‐phosphate (PtdIns‐3‐P) is considered as a lipid constitutively present on endosomes; it does not seem to have a dynamic role in signalling. In contrast, phosphatidylinositol‐3,4,5‐trisphosphate (PtdIns‐3,4,5‐P 3 ) plays a crucial role in different signalling pathways including translocation of the glucose transporter protein GLUT4 to the plasma membrane upon insulin receptor activation. GLUT4 translocation requires activation of two distinct pathways involving phosphatidylinositol 3‐kinase (PI 3‐K) and the small GTP‐binding protein TC10, respectively. The contribution of each pathway remains to be elucidated. Here we show that insulin specifically induces the formation of PtdIns‐3‐P in insulin‐ responsive cells. The insulin‐mediated formation of PtdIns‐3‐P occurs through the activation of TC10 at the lipid rafts subdomain of the plasma membrane. Exogenous PtdIns‐3‐P induces the plasma membrane translocation of both overexpressed and endogenous GLUT4. These data indicate that PtdIns‐3‐P is specifically produced downstream from insulin‐mediated activation of TC10 to promote the plasma membrane translocation of GLUT4. These results give a new insight into the intracellular role of PtdIns‐3‐P and shed light on some aspects of insulin signalling so far not completely understood.