ITT Istituto Toscano Tumori (logo)
Ricerca avanzata
 

Signal Transduction

Istituto Toscano Tumori
Via Fiorentina, 1
53100 - Siena - Italy
Ph: +39 0577 1916274
Fax: +39 0577 43444

Principal Investigator: Mario Chiariello, MD, PhD

staff picture   Staff

The Unit is placed inside the Toscana Life Sciences (TLS) Foundation building, located in Siena, in the historical area of the "Torre Fiorentina" Science Park, where Novartis Vaccines and Diagnostics Srl has today concentrated its Research & Development activities. Since 2002, the area has also been hosting Sienabiotech S.p.A. and the Molecular Biology Department of the University of Siena. All together, over 350 researchers are currently working at the "Torre Fiorentina" Campus, which offers state-of-the art technological platforms, scientific equipment and support services.

Main Research Themes

MAP kinases are a family of proline-directed serine/threonine kinases that play a central role in signal transduction in all eukaryotic cells, from yeast to humans. They coordinate signaling from a variety of extracellular and intracellular stimuli controlling the activity of a vast array of cellular regulatory proteins including protein kinases, transcription factors, cytoskeletal proteins and other enzymes.

Erk8 is the last identified member of the MAP kinase family of proteins. Expressed in several human tissues, its activity can be modulated by serum, H2O2 and different activated oncogenes. Recent data also point to a role for Erk8 in the control of the protein levels and functions of different nuclear receptors among which androgen, glucocorticoid and oestrogen receptors. In particular, Erk8 strongly enhances degradation of the oestrogen receptor-alpha (ER-alpha) and loss of the MAP kinase has been correlated to breast cancer progression. Ultimately, although possessing a very typical MAP kinase domain, Erk8 also presents a peculiarly long C-terminal domain containing two putative SH3-binding sites.

Recently, we showed that three human oncogenes, RET/PTC3, RET/MEN2B and bcr/abl, are able to activate Erk8 and we localized the region responsible for the modulation of the activity of this kinase by the RET- and Abl-derived oncogenes in the Erk8 C-terminal domain. Still, the identity of its upstream activators and downstream effectors is almost completely unknown. Likewise, the mechanisms controlling the activity of this MAP kinase and its biological functions have yet to be defined.

The goal of this Unit is to achieve a comprehensive characterization of the mechanisms contributing to the regulation of cell growth and transformation by MAP kinases and, in particular, by Erk8. The central hypothesis is that the Erk8 MAP kinase is able to control different signal transduction pathways based on its kinase activity and on its ability to physically interact with other enzymes and scaffolding proteins. Through these activities, we expect that Erk8 will control several aspects of cell life among which cell proliferation and transformation. Therefore, the rationale for the proposed research is that full understanding of the signal transduction mechanisms governing the activity of Erk8 and of its downstream targets may, in the near future, help in generating a rationale approach to the management of tumors whose pathogenesis depends on the production of molecular information through this signaling pathway. Also, Erk8 is expected to function as a key integration point, receiving signals from several independent transduction pathways and controlling different cellular functions. To accomplish the goal of this Unit, we plan to pursue the following main objectives:

  1. To unravel basic signal transduction mechanisms regulating the activity of the Erk8 protein.
  2. To identify Erk8 specific substrates and interacting proteins.
  3. To define the role of Erk8 in cell proliferation and human cancer.

Through these studies, we expect to establish novel Erk8-dependent signaling pathways involved in controlling different aspects of both normal and cancer cell growth. This is important because it is expected to have significant positive effects on human health, by allowing the development of new pharmacological strategies that are designed to target tumors whose pathogenesis and/or survival depends fully or in part on signals modulated by Erk8. Indeed, interest in protein kinases as drug targets has recently exploded. Among them, several pharmacological inhibitors have been developed targeting MAP kinase pathways. Pharmacological inhibitors have been, in fact, identified acting on the ERKs, p38s, JNKs and ERK5. Several of these inhibitors have been effective in animal models and have therefore advanced to clinical trials for the treatment of inflammatory diseases and cancer. Understanding the machinery involved in the regulation of Erk8 activity and the biological processes they participate to will therefore provide us a rationale for the development of pharmacological inhibitors for Erk8 and, hopefully, for their use for prevention and therapeutic intervention. At the same time, fundamental new knowledge will be obtained that is expected to significantly advance the general field regarding the biology of MAP kinases and of their intracellular signaling intermediates.

Publications

  1. Marinissen M.J., Chiariello, M., and Gutkind J.S. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38gamma) MAP kinase pathway (2001). Genes Dev., 15: 535-553.
  2. Chiariello M., Marinissen M.J. and Gutkind J.S. Regulation of c-myc expression by PDGF through the Src-mediated activation of Vav2 and Rho GTPases (2001). Nat. Cell. Biol., 3: 580-586.
  3. Chiariello M., and Gutkind J.S. Regulation of MAP Kinases by G Protein-Coupled Receptors (2002). Methods in Enzymology, 345: 437-447
  4. Iavarone C., Catania A., Marinissen M.J., Visconti R., Acunzo M., Tarantino C., Carlomagno M.S., Bruni C.B., Gutkind J.S. and Chiariello M. The platelet-derived growth factor controls c-myc expression through a JNK- and AP-1-dependent signaling pathway (2003). J. Biol. Chem. 278: 50024-50030.
  5. Marinissen M.J., Chiariello M., Tanos T., Bernard O., Narumiya S., and Gutkind J.S. The small GTP-binding protein RhoA regulates c-Jun by a ROCK-JNK signaling axis (2004). Molecular Cell. 13: 29-41.
  6. Bucci C. and Chiariello M. Signal transduction gRABs attention (2006). Cellular Signalling. 18: 1-8.
  7. Marinissen M.J. and Chiariello M. Targeting MAP kinase signaling pathways for the treatment of cancer (2006). In: "Signalling molecules as targets in cancer therapy" by Nova Science Publishers Inc.
  8. Catania A. Iavarone C., Carlomagno M.S. and Chiariello M. Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity (2006). Biochem. Biophys. Res. Commun. 343: 544-554.
  9. Iavarone C., Acunzo M., Carlomagno F., Catania A., Melillo R.M., Carlomagno M.S., Santoro M. and Chiariello M. Activation of the Erk8 MAP kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene (2006). J Biol Chem. 281:10567-10576.

Collaborations

  • Istituto di Endocrinologia e Oncologia Sperimentale "G. Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
  • Universita' degli Studi di Napoli "Federico II", Italy
  • National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
  • IFOM-IEO, Milano, Italy

^ torna all'inizio