Arcaro
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Onkologie, Abteilung » Prof. Dr. Felix Niggli » Arcaro
Completed research project
| Title / Titel | Signalling by class II phosphoinositide 3-kinases downstream of receptor tyrosine kinases | ||
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | The phosphoinositide 3-kinase (PI3K) family comprises three classes of enzymes, which are key signalling molecules controlling a variety of cell responses including growth, survival, differentiation, migration and metabolism. Class IA and II PI3Ks associate with and are activated by polypeptide growth factor receptors (GFRs). While the molecular mechanism of class IA PI3K activation and docking to GFRs are well understood, these events are poorly understood in the case of class II enzymes. Our preliminary data have also shown that Src family non-receptor tyrosine kinases phosphorylate and activate the class II PI3KC2beta in vitro and in vivo. The biological functions of class II PI3Ks remain generally unclear, although our recently published work has described a role for PI3KC2beta in activation of protein kinase B (PKB)/Akt by polypeptide growth factor receptors. Our working hypothesis is that class II PI3Ks mediate some of the biological responses to polypeptide growth factors by associating with GFRs and generating 3-phosphorylated polyphosphoinositides second messengers. These in turn activate specific downstream targets such as PKB/Akt . Here we aim to investigate : (1) What domain(s) of class II PI3Ks mediate association with GFRs, and whether adapter molecules are required for this interaction. (2) The molecular mechanism of class II PI3Ks enzymatic activation. (3) To gain further insight into the biological role of PI3KC2beta in the context of the whole organism, we will use gene knockout technology to generate a mouse with a targeted deletion of the mouse PI3KC2beta gene. The studies described in the present proposal will hopefully underscore the differences in the molecular mechanisms of enzymatic activation and biological functions between the various classes of PI3Ks in vivo, and thus contribute to a better understanding of the cellular functions of these key signalling molecules. |
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| Publications / Publikationen | Katso, R.M., Pardo, O.E., Palamidessi, A., Franz, C., Marinov, M., De Laurentiis, A., Downward, J., Scita, G., Ridley, A.J., Waterfield, M.D., and Arcaro, A. (2006). Phosphoinositide 3-kinase C2beta Regulates Cytoskeletal Organization and Cell Migration via Rac-dependent Mechanisms. Mol. Biol. Cell, 17, 3729-3744Arcaro, A., Aubert, M., Espinosa del Hierro, M.E., Khanzada, U.K., Angelidou, S., Tetley, T.D., Bittermann, A.G., Frame, M.C., and Seckl, M.J. (2007). Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signaling. Cell. Signal., in press, doi: 10.1016/j. cellsig.2006.12.003Doepfner, K.T., Boller, D., De Laurentiis, A., Guerreiro, A.S., Marinov, M., and Arcaro, A. (2007). Recent Patents of Gene Sequences Relative to the Phosphatidylinositol 3-kinase / Akt Pathway and their Relevance to Drug Discovery. Recent Patents on DNA & Gene Sequences, 1, 9Arcaro, A., Khanzada, U.K., Vanhaesebroeck, B., Tetley, T.D., Waterfield, M.D., and Seckl, M.J. (2002). Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation. EMBO J., 21, 5097-5108Arcaro, A., Zvelebil, M.J., Wallasch, C., Ullrich, A., Waterfield, M.D. and Domin, J. (2000). Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol. Cell. Biol., 20, 3817-3830Arcaro, A., Volinia, S., Zvelebil, M.J., Stein, R., Gout, I., Layton, M.J., Ahmadi, K., Watton, S.J., Downward, J. and Waterfield, M.D. (1998). Human phosphoinositide 3-kinase C2beta, the role of calcium and the C2 domain in enzyme activity. J. Biol. Chem., 273, 33082-33090 | ||
| Keywords / Suchbegriffe | phosphoinositide 3-kinase, growth factor receptor , protein kinase B/Akt, tyrosine phosphorylation, gene knockout | ||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.kispi.uzh.ch/onkologie/ http://www.cnz.uzh.ch/arcaro.html | ||
| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) Hartmann-Muller Stiftung fur Medizinische Forschung |
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| Duration of Project / Projektdauer | Jan 2005 to Dec 2009 |