Signal Transduction group
Structure and function of Cytokine receptors
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Stefan N.
CONSTANTINESCU, Member
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the group ...
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Alumni
Nancy CACERES, Research Associate
Carmen DIACONU, Postdoctoral
Fellow
Katharina KUBATZKY, Postdoctoral
Fellow
Virginie MOUCADEL, Postdoctoral
Fellow (Marie Curie Fellow)
Alexandra DUSA, PhD Student
Yohan ROYER, PhD Student
Judith STAERK, PhD Student
Nadine SEUBERT, Student, (Univ.
Würzburg, Germany)
Mingli LI, Research Assistant
Yan YIN, Research Assistant
Marie Hanon, Technician
Catherine MENU, Technician
Loic GARCON, Marie Curie Visiting
Student, Institut Gustave Roussy, France
Yaniv MALKA, Marie Curie Visiting
Student, Tel-Aviv University, Israel
Marcel COSTULEANU, Iasi
University Medical School, Romania
Cytokines and their receptors are critical for the formation of mature blood cells and for the function of the immune system. Signaling by cytokine receptors is triggered by ligand-induced changes in receptor dimerization/oligomerization, which induces the activation of cytosolic Janus tyrosine kinases (JAK).
The group led by Stefan Constantinescu is studying the signal transduction mechanisms and biologic functions of cytokine receptors such as the receptors for erythropoietin (Epo), thrombopoietin (Tpo), interleukin 2 (IL2) and interleukin 9 (IL9R). The assembly of cell-surface receptor complexes, the structure and orientation of the transmembrane (TM) and cytosolic juxtamembrane (JM) domains, and the regulation by JAK kinases of receptor traffic are major focuses.
The group is actively investigating the mechanisms by which a JAK2 point mutant induces Polycythemia Vera and myeloproliferative diseases in humans, as well as the role of TpoR mutants in myelofibrosis.
- The mechanisms by
which a mutant JAK2 induces Polycythemia Vera and
myeloproliferative diseases in humans
Judith Staerk, Christian Pecquet - Involvement of TpoR in
myeloproliferative diseases
Judith Staerk, Michael Girardot - Determination of
the interface and orientation of the activated EpoR
and TpoR dimers
Judith Staerk, Katharina Kubatzky, Virginie Moucadel and Alexandra Dusa - Structural studies on
the transmembrane and juxtamembrane cytosolic
sequences of the EpoR
Katharina Kubatzky, Alexandra Dusa - Traffic of
cytokine receptors to the cell-surface: the common γ
chain (γc) of the IL2/IL9 receptor complexes and
TpoR
Yohan Royer, Carmen Diaconu, Christian Pecquet - Random mutagenesis
approaches to study interactions between transmembrane
domains and structure of JAK2 V617F
Alexandra Dusa - Constitutive
activation of JAK-STAT signaling pathways and genes
targeted by STAT5 in transformed hematopoietic and
patient-derived leukemia cells
Virginie Moucadel, Michael Girardot
Selected publications
- Royer, Y., J. Staerk, M. Costuleanu, P. J. Courtoy, and S. N. Constantinescu. Janus kinases affect thrombopoietin receptor cell surface localization and stability. J. Biol. Chem. 2005;280:27251.
- James, C., V. Ugo, J. P. Le Couedic, J. Staerk, F. Delhommeau, C. Lacout, L. Garcon, H. Raslova, R. Berger, A. Bennaceur-Griscelli, J. L. Villeval, S. N. Constantinescu, N. Casadevall, and W. Vainchenker. 2005. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144.
- Vainchenker, W., and S. N. Constantinescu. A unique activating mutation in JAK2 is at the origin of Polycythemia Vera and allows a new classification of myeloproliferative diseases. Hematology (Am. Soc. Hematol. Educ. Program) 2005;:195.
- Zhao, Z. J., S. B. Krantz, W. Vainchenker, N. Casadevall, and S. N. Constantinescu. Role of tyrosine kinases and phosphatases in Polycythemia Vera. Semin. Hematol. 2005;42:221.
- Staerk, J., A. Kallin, J.-B. Demoulin, W. Vainchenker, and S. N. Constantinescu. JAK1 and Tyk2 activation by the homologous Polycythemia Vera JAK2 V617F mutation: cross-talk with IGF1 receptor. J. Biol. Chem. 2005;280:41893.
- Staerk, J., C. Lacout, S. O. Smith, W. Vainchenker, and S. N. Constantinescu. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood 2005;107:1864.
- Kubatzky, K. F., W. Liu, K. Goldgraben, C. Simmerling, S. O. Smith, and S. N. Constantinescu. Structural requirements of the extracellular to transmembrane domain junction for erythropoietin receptor function. J. Biol. Chem. 2005;280:14844.
- Moucadel, V., and S. N. Constantinescu. Differential STAT5 signaling by ligand-dependent and constitutively active cytokine receptors. J Biol Chem 2005;280:13364.
- Seubert, N., Y. Royer, J. Staerk, K. F. Kubatzky, V. Moucadel, S. Krishnakumar, S. O. Smith, and S. N. Constantinescu. Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. Mol. Cell 2003;12:1239.
- Constantinescu, S. N., T. Keren, W. P. Russ, I. Ubarretxena-Belandia, Y. Malka, K. F. Kubatzky, D. M. Engelman, H. F. Lodish, and Y. I. Henis. The erythropoietin receptor transmembrane domain mediates complex formation with viral anemic and polycythemic gp55 proteins. J Biol Chem 2003;278:43755.
- Constantinescu, S. N., T. Keren, M. Socolovsky, H. Nam_, Y. I. Henis, and H. F. Lodish. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc. Natl. Acad. Sci. USA 2001;98:4379.
- Constantinescu, S. N., L. J. Huang, H. Nam, and H. F. Lodish. The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol. Cell 2001;7:377.
- Huang, L. J., S. N. Constantinescu, and H. F. Lodish. 2001. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol. Cell 2001;8:1327.
- Constantinescu, S. N., X. Liu, W. Beyer, A. Fallon, S. Shekar, Y. I. Henis, S. O. Smith, and H. F. Lodish. Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain. EMBO J 1999;18:3334.