Signal Transduction & Molecular Hematology
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Group Leader Stefan Constantinescu Contact Stefan Constantinescu Ludwig Insitute for Cancer Research and de Duve Institute Université catholique de Louvain Avenue Hippocrate 74, UCL 75-4 B-1200 Brussels phone (direct) : 32 (0)2 764 75 40 fax : 32 (0)2 764 65 66 e-mail: Stefan Constantinescu Group members > |
Research topics
Formation of blood cells is tightly controlled by cytokines and their specific receptors. Our goal is to understand how activation of cytokine receptors such as those for erythropoietin (EpoR) and thrombopoietin (TpoR), is transmitted to Janus kinases (JAKs), STATs and other downstream pathways to regulate survival, proliferation and differentiation of blood progenitors.
1. Orientation-dependent signaling of cytokine receptor: Ligand-imposed dimerization seems to be at the core of cytokine receptor activation. Using coiled coils we can impose predictable dimeric or tetrameric interfaces to the transmembrane and cytosolic domains of receptors and then test signaling and biologic effects of each conformation. Not only fully active conformations and their signaling outputs were identified, but also conformations that are partially active, that could be useful pharmacologically. We find that receptor sequences flanking the transmembrane domains function as switches for signaling activation and termination and aim to target them for pharmacologic modulation of receptor signaling.
2. Physiologic versus oncogenic signaling: Physiologic cytokine signaling is always transient. In contrast, mutations that permanently activate signaling of cytokine receptors are oncogenic. The reasons for the latter are not known. Using signaling assays, classical molecular biology and chromatin immunprecipitation we attempt to identify gene promoters that are targeted by the JAK-STAT pathway only in transformed cells.
3. JAK2 V617F and human myeloproliferative diseases: We and others have identified activating mutations in JAK2 (V617F) and in TpoR that are responsible for the majority of human myeloproliferative diseases such as Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). In these diseases, excessive numbers of red blood cells, platelets and granulocytes are formed, in the absence of cytokine stimulation. We try to understand how can one active mutant, JAK2 V617F, induce three related, but distinct, diseases and how do they evolve to acute leukemia. Furthermore, we aim to develop assays that can lead to identification of small molecules that only target JAK2 V617F for inhibition, and not wild type JAK2, which is crucial for blood formation.
To know more... (pdf chapter of the last de Duve Institute report)
