Signal transduction
ITT Core Research Laboratory (CRL)
Azienda Ospedaliero Universitaria Senese (AOU Senese)
Via Fiorentina, 1 - 53100, Siena
Tel: 0577 231274
Fax: 0577 280599
Principal investigator: Mario Chiariello, MD, PhD
| Team members | |
|---|---|
| David Colecchia | PhD student |
| Angela Strambi | PhD, Post-doctoral fellow |
| Matteo Rossi | PhD student |
| Sveva Sanzone | PhD |
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 (a). 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 (a) (Figure 1).
Erk8 is the last identified member of the MAP kinase family of proteins. Expressed in several human tissues, its activity can be modulated by DNA-damaging agents and different activated oncogenes (b,c). Indeed, we have already shown that three human oncogenes, RET/PTC3, RET/MEN2B and bcr/abl, are able to activate Erk8 (b) while, in turn, this MAP kinase controls the activity of different nuclear receptors (d,e) (Figure 2). Interestingly, Erk8 has been recently involved in transformation in human
Figure 1 - Schematic illustration of the three-modular organization of MAP kinase (MAPK) cascades in which a MAPK kinase kinase (MEKK) modulates the activity of a MAPK kinase (MEK), which subsequently activates a MAP kinase, resulting in phosphorylation of downstream substrates
Figure 2 - Schematic representation of the currently known oncogenes and signaling pathways impinging on the regulation of Erk8. In turn, this MAP kinase controls the expression and activity of different nuclear receptors. Human tumors, currently studied because correlated to Erk8 functions, are also indicated
colon cancer cells. 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. Therefore, we expect that full understanding of the signal transduction mechanisms governing the activity of Erk8 and its downstream targets will, in the near future, help in generating a rational approach to the management of tumors whose pathogenesis depends on the production of molecular information through this molecule.
To accomplish the goal of the Unit, we are pursuing the following research themes.
Unraveling basic signal transduction mechanisms involving the Erk8 protein
MAP kinases are able to control different signal transduction pathways based on their enzymatic activity and their ability to physically interact with other enzymes and scaffolding proteins (a). Erk8 is therefore expected to function as a key integration point, receiving signals from several independent transduction pathways and controlling different processes, such as cell proliferation and transformation. In our effort to identify Erk8-specific substrates and interacting proteins, using a two-hybrid approach, we have already discovered and validated several clones, among which transcription factors, trans-membrane proteins and nuclear receptors. In general, several of these proteins have already been involved in the control of cell proliferation, metabolism and neurodegenerative diseases and represent interesting potential targets for Erk8 functions, particularly in cell transformation.
Unraveling the role of Erk8 in Abl-dependent signaling pathways and in human Hematological malignancies
Based on our data showing the ability of the Bcr/Abl oncogene to interact and modulate Erk8 activity (b), we are addressing the role of Erk8 during the tumorigenic process sustained by this human oncogene and how it would be possible for us to interfere, generating a rational approach to the management of these tumors.
Studying the toll of Erk8 in mammary gland physiology and cancer
Erk8 has been recently correlated to the control of the protein levels and functions of different nuclear receptors, among which androgen, glucocorticoid and estrogen (d,e). Erk8 also strongly enhances degradation of the estrogen receptor-alpha, and loss of the MAP kinase has been correlated to breast cancer progression (e). Based on this information and on our preliminary results, we are addressing the role of Erk8 in breast cancer and characterizing novel Erk8-dependent signaling pathways contributing to this disease.
Using ERK8 as molecular target to select specific pharmacological inhibitors
We are building a homology model structure of the catalytic domain of Erk8 to be used to screen libraries of kinase inhibitors, to select drugs showing in silico selectivity for this MAP kinase. Once obtained, we will first test them on Erk8 and then examine the capacity of such inhibitors to affect proliferation and resistance of human cancer cells to chemotherapy, to develop novel therapeutic approaches to human malignancies. Through these studies, we expect to establish novel Erk8-dependent signaling pathways involved in controlling different aspects of both normal and cancer cell growth.
Understanding the mechanism involved in the regulation of Erk8 activity and the biological processes they participate in will therefore provide us a rationale for 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. Supporting this approach, several pharmacological inhibitors have already been developed, targeting other MAP kinases, and some of these inhibitors have already been effective in animal models and have therefore advanced to clinical trials for the treatment of inflammatory diseases and cancer. 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 their intracellular signaling intermediates.
References
- Widmann C, Gibson S, Jarpe MB, Johnson GL: Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999; 79: 143-80.
- Iavarone C, Acunzo M, Carlomagno F, et al: Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. J Biol Chem 2006; 281: 10567-76.
- Klevernic IV, Martin NM, Cohen P: Regulation of the activity and expression of ERK8 by DNA damage. FEBS Lett 2009; 583: 680-4.
- Saelzler MP, Spackman CC, Liu Y, Martinez LC, Harris JP, Abe MK: ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5. J Biol Chem 2006; 281: 16821-32.
- Henrich LM, Smith JA, Kitt D, et al: Extracellular signal-regulated kinase 7, a regulator of hormonedependent estrogen receptor destruction. Mol Cell Biol 2003; 23: 5979-88.
Research grants
| Year | Funding Agency | Amount |
|---|---|---|
| 2010-2012 | Ministero del lavoro,della salute e delle politiche sociali | |
| 2011-2013 | Ministero del lavoro,della salute e delle politiche sociali | |
| 2011-2013 | Regione Toscana | |
| 2007-2010 | Istituto Toscano Tumori | |
| 2004-2007 | Associazione Italiana per la Ricerca sul Cancro (AIRC) |
Main collaborations
With units within ITT
- Clinical Physiology Institute, Consiglio Nazionale delle Ricerche (CNR), Siena
- Department of Experimental Pathology and Oncology, University of Florence
With other Italian and foreign units
- Endocrinology and Experimental Oncology Institute, CNR, Napoli
- Fondazione IFOM, Istituto Europeo di Oncologia (IEO), Milano
- Department of Biology and Molecular Pathology, "Federico II" University, Napoli
- National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH) (USA)
- Laboratorio de Oncología Molecular, Universidad de Castilla-La Mancha, Albacete (Spain)
Publications
- Rossi M, Colecchia D, Iavarone C, Strambi A, Piccioni F, Verrotti di Pianella A, Chiariello M. Extracellular signal-regulated kinase 8 (ERK8) controls estrogen-related receptor a (ERRa) cellular localization and inhibits its transcriptional activity. J Biol Chem, 2011. 286: 8507-8522.
- Acunzo M, Visone R, Romano G, Veronese A, Lovat F, Palmieri D, Bottoni A, Garofalo M, Gasparini P, Condorelli G, Chiariello M and Croce CM miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene, 2011. Jun 27 (Epub ahead of print).
- Chiariello M, Vàque JP, Crespo P, Gutkind JS. Activation of Ras and Rho GTPases and MAP Kinases by G-protein-coupled receptors. Methods Mol Biol., 2010. 661: 137-50.
- Catania A, Iavarone C, Carlomagno MS, Chiariello M: Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. Biochem Biophys Res Commun 2006; 343: 544-54.
- Marinissen MJ, Chiariello M: Targeting MAP kinase signaling pathways for the treatment of cancer. In Signalling molecules as targets in cancer therapy, Nova Science Publishers Inc., 2006.
- Bucci C, Chiariello M: Signal transduction gRABs attention. Cellular Signalling 2006; 18: 1-8.
- Iavarone C, Catania A, Marinissen MJ, et al: The platelet-derived growth factor controls c-myc expression through a JNK- and AP-1-dependent signaling pathway. J Biol Chem 2003; 278: 50024-30.
- Chiariello M, Gutkind JS: Regulation of MAP kinases by G protein-coupled receptors. Methods in Enzymolog 2002; 345:437-47.
- Chiariello M, Marinissen MJ, Gutkind JS: Regulation of c-myc expression by PDGF through the Src-mediated activation of Vav2 and Rho GTPases. Nat Cell Biol 2001; 3: 580-6.
