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Inositide Signalling Group
Group Leaders:
Research field
Our interests focus on the following areas.
The role of phosphoinositide 3-kinases (PI 3-Ks) in insulin signalling and diabetes
Although it has long been known that genetic factors play a determinant role in this disease, the underlying mechanisms responsible for insulin resistance are still poorly defined. One crucial function of insulin is disposal of glucose into adipose and muscle that is obtained through movement of a glucose transporter (GLUT4) to the cell surface (translocation). This process appears to fail in insulin resistance accompanying several forms of diabetes. We have recently demonstrated that insulin specifically generates the lipid phosphatidylinositol-3-phosphate (PtdIns-3-P) that in turn plays a key role in GLUT4 translocation. Our study is currently investigating the mechanism involved in the insulin-dependent generation and the precise mechanism of action of PtdIns-3-P.
The role of class II PI 3-Ks in intracellular signalling
Phosphoinositide 3-kinases (PI 3-Ks), the family of enzymes responsible for generation of 3-phosphorylated phosphoinositides, are crucial components of many intracellular signalling pathways and play key roles in many different physiological events. Furthermore altered PI 3-K-dependent pathways are implicated in different diseases including cancer and diabetes. Three classes of PI 3-Ks exist although the majority of studies have been focused so far on members of class I and their main in vivo product phosphatidylinositol-3,4,5-trisphosphate. There is currently an increasing interest on the members of class II PI 3-K since several lines of evidence suggest a potential role for these enzymes in agonist-mediated regulation of cellular functions. However, a clear mechanism of activation and the precise intracellular functions of these enzymes are still not defined. Furthermore there is no clear indication of their in vivo lipid products. We are currently studying the role of these isoforms in different intracellular signalling pathways.
The role of PI 3-K-mediated regulation of phospholipase C
Several line of evidence suggest that the enzyme phospholipase C g 1 (PLC g 1) is implicated in tumourigenesis. Activation of PLC g 1 occurs through receptor tyrosin kinases activation and it generally involves phosphorylation of PLC g 1. In addition, PI 3-K can regulate PLC g 1 activity in a mechanism mediated by the interaction of phosphatidylinositol-3,4,5-trisphosphate and PLC g 1 pleckstrin homology domain. We have reported that such PI 3-K-mediated regulation of PLC g 1 has a specific role in migration of breast cancer cells. We are currently investigating the role of the PI 3-K/ PLC g 1 pathway in different systems, including endothelial and stem cells.
Development of specific inhibitors of PI 3-K-dependent pathways
PI 3-K is an attractive target for the development of anticancer drugs because of its central role in signalling pathways necessary for both cell growth and transformation. It is noteworthy that the tumor suppressor protein PTEN, whose gene is deleted or mutated in a wide variety of human cancers, possesses a 3-phosphoinositide-phosphatase activity. This has highlighted the potential pharmacological importance of PI 3-K inhibitors. We have recently developed a strategy to specifically block PI 3-K-mediated activation of target proteins based on the use of exogenous inositol polyphosphates. Our aim is to examine the consequences of the inhibition of this pathway in human cancer cells.
Key research papers
1 Maffucci T, Falasca M. (2007) Phosphoinositide 3-kinase-dependent regulation of phospholipase Cgamma. Biochem Soc Trans. 35:229-230.
2 Falasca M, Maffucci T. (2007) Role of class II phosphoinositide 3-kinase in cell signalling. Biochem Soc Trans. 35:211-214.
3 Falasca M, Maffucci T. (2006) Emerging roles of phosphatidylinositol 3 monophosphate as a dynamic lipid second messenger. Arch Physiol Biochem. 112:274-284.
4 Maffucci T., Piccolo E., Cumashi A., Iezzi M., Riley A.M., Saiardi A. Godage H.Y., Rossi C., Broggini M., Iacobelli S., Potter B.V.L., Innocenti P. and Falasca M. (2005) Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by Inositol pentakisphosphate results in ant-angiogenic and anti-tumour effects. Cancer Res, 65 : 8339-8349.
5 Maffucci, T., Cooke, F.T., Foster, F.M., Traer, C.J., Fry, M.J., and Falasca M. (2005) Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J Cell Biol. , 169 :789-799.
6 Piccolo E., Vignati S., Maffucci, T., Innominato P.F., Riley A.M., Potter B.V.L., Pandolfi P.P., Broggini M., Iacobelli S., Innocenti P. and Falasca M. ( 2004 ) Inositol Pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Oncogene , 23 :754-1765.
7 Okigaki, M., Davis , C., Falasca, M. , Harroch, S., Felsenfeld, D.P., Sheetz, M.P, and Schlessinger, J. (2003) Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci USA , 100:10740-10745.
8 Maffucci, T., Razzini, G., Ingrosso, A. Chen, H., Iacobelli, S., Sciacchitano, S., Quon, M.J. and Falasca, M. (2003) Role of Pleckstrin Homology domain in regulating membrane targeting and metabolic function of insulin receptor substrate-3. Mol. End ., 17: 1568-1579.
9 Maffucci, T., Brancaccio, A., Piccolo, E., Stein, R.C. and Falasca, M. (2003) Insulin induces phosphatidylinositol 3-phosphate formation through TC10 activation . EMBO J ., 22: 4178-89.
10 Piccolo, E., Innominato, P.F., Mariggio, M.A., Maffucci, T., Iacobelli, S. and Falasca, M. (2002) The mechanism involved in the regulation of phospholipase Cgamma1 activity in cell migration. Oncogene , 21 :6520-6529.
11 Razzini, G., Brancaccio, A., Lemmon, M.A., Guarnieri, S. and Falasca, M. (2000) The role of the Pleckstrin Homology (PH) domain in membrane-targeting and activation of phospholipase Cb1. J. Biol. Chem ., 275 :14873-14881.
12 Razzini, G., Berrie, C.P., Vignati, S., Broggini, M., Mascetta, G., Brancaccio A. and Falasca, M. (2000) Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines. FASEB J ., 14 :1179-1187.
13 Falasca, M. , Logan , S.K., Lehto, V.P., Baccante, G., Lemmon M.A. and Schlessinger, J. (1998) Activation of phospholipase Cg1 by PI3-kinase induced PH domain mediated membrane targeting. Embo J., 17 : 414-422.
