Gabriel Levy, Serge Carillo, Benjamin Papoular, Bruno Cassinat, Jean‐Marc Zini, Emilie Leroy, Leila N. Varghese, Ilyas Chachoua, Jean‐Philippe Defour, Steven O. Smith, Stefan N. Constantinescu,
Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate ...
Tópico(s): Kruppel-like factors research
2020 - Elsevier BV | Blood
Jean‐Philippe Defour, Miki Itaya, Vitalina Gryshkova, Ian Brett, C. Pecquet, Takeshi Sato, Steven O. Smith, Stefan N. Constantinescu,
Dimerization of single-pass membrane receptors is essential for activation. In the human thrombopoietin receptor (TpoR), a unique amphipathic RWQFP motif separates the transmembrane (TM) and intracellular domains. Using a combination of mutagenesis, spectroscopy, and biochemical assays, we show that W515 of this motif impairs dimerization of the upstream TpoR TM helix. TpoR is unusual in that a specific residue is required for this inhibitory function, which prevents receptor self-activation. Mutations ...
Tópico(s): Renal Diseases and Glomerulopathies
2013 - National Academy of Sciences | Proceedings of the National Academy of Sciences
Judith Staerk, Jean‐Philippe Defour, C. Pecquet, Emilie Leroy, Hélène Antoine‐Poirel, Ian Brett, Miki Itaya, Steven O. Smith, William Vainchenker, Stefan N. Constantinescu,
Tópico(s): Myeloproliferative Neoplasms: Diagnosis and Treatment
2011 - Springer Nature | The EMBO Journal
Jean‐Philippe Defour, Gabriel Levy, Emilie Leroy, Steven O. Smith, Stefan N. Constantinescu,
Tópico(s): Kruppel-like factors research
2019 - Springer Nature | Leukemia
Emilie Leroy, Jean‐Philippe Defour, Takeshi Sato, Sharmila Dass, Vitalina Gryshkova, Myat Marlar Shwe, Judith Staerk, Stefan N. Constantinescu, Steven O. Smith,
Ligand binding to the extracellular domain of the thrombopoietin receptor (TpoR) imparts a specific orientation on the transmembrane (TM) and intracellular domains of the receptors that is required for physiologic activation via receptor dimerization. To map the inactive and active dimeric orientations of the TM helices, we performed asparagine (Asn)-scanning mutagenesis of the TM domains of the murine and human TpoR. Substitution of Asn at only one position (S505N) activated the human receptor, whereas ...
Tópico(s): Renal Diseases and Glomerulopathies
2015 - Elsevier BV | Journal of Biological Chemistry
Gabriel Levy, Serge Carillo, Benjamin Papoular, Emilie Leroy, Jean‐Philippe Defour, Steven O. Smith, Stefan N. Constantinescu,
Background: Thrombopoietin receptor (TpoR) is a type‐I dimeric cytokine receptor that regulates platelet formation and hematopoietic stem cell renewal. Tpo binding mediates TpoR dimerization, which imparts a specific orientation on the receptor transmembrane (TM) and intracellular (IC) domains that leads to JAK2 trans‐phosphorylation. Mutations in key amino acids in the TpoR TM or cytosolic juxtamembrane (JM) domains lead to myeloproliferative neoplasms. The study of such W515K/L/A/R/S mutants at the ...
Tópico(s): Platelet Disorders and Treatments
2019 - Wolters Kluwer | HemaSphere
Jean‐Philippe Defour, Emilie Leroy, Sharmila Dass, Thomas Balligand, Gabriel Levy, Ian Brett, Nicolas Papadopoulos, Céline Mouton, Lidvine Genet, C. Pecquet, Judith Staerk, Steven O. Smith, Stefan N. Constantinescu,
Dimerization of the thrombopoietin receptor (TpoR) is necessary for receptor activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations of the transmembrane (TM) helices within a receptor dimer can lead to different signaling outputs. Here we addressed the structural basis of activation for receptor mutations S505N and W515K that induce myeloproliferative neoplasms. We show using in vivo bone marrow reconstitution experiments that ligand- ...
Tópico(s): Lipid metabolism and disorders
2023 - eLife Sciences Publications Ltd | eLife
A. Barbaud, Pauline Girault, J.‐L. Schmutz, F. Weber‐Muller, P. Tréchot,
... 135–138. 5 Tomb R R, Grosshans E, Defour E, Heid E. Allergic skin reaction to tetrazepam ... D C, Johnson C R, Lebel N A, Stevens C L. Chimie Organique. Volume I: Structure Des ...
Tópico(s): Dermatology and Skin Diseases
2009 - Wiley | Contact Dermatitis
Gabriel Levy, Nicolas Papadopoulos, C. Pecquet, Jean‐Philippe Defour, Emilie Leroy, Nabih Maslah, Bruno Cassinat, Steven Escar Smith, Stefan N. Constantinescu,
Specific mutations in the thrombopoietin receptor (TpoR/MPL) are responsible for 2% of essential thrombocythemia (ET) and 5% of primary myelofibroses (PMF). The most prevalent oncogenic mutations, W515K/L/R/S/A and S505N, occur in the transmembrane domain (TMD) of TpoR. They lead to dimerization of TpoR in an active conformation in absence of its ligand, thrombopoietin (Tpo), and activation of downstream signaling mainly through the JAK/STAT pathway. We demonstrated the critical role of residue W491 ...
Tópico(s): Platelet Disorders and Treatments
2022 - Elsevier BV | Blood
Tom Defour, Sofia Scataglini, Liora Peres, Nick Meertens, Stijn Verwulgen, Steven Truijen,
Prolonged inadequate sitting posture together with overuse and repetitive strain cause musculoskeletal disorders and pain in pianists. Nowadays wearable sensors based on miniaturized Inertial Measurement Units combined with video recording can provide real time information of the performer in a non-intrusive way and ecological approach without affecting the performance of the user. Therefor teachers can use this information to monitor their students during classes and practice and give adjustments. ...
Tópico(s): Occupational health in dentistry
2020 - Springer Nature | Advances in intelligent systems and computing
Jean‐Philippe Defour, Miki Itaya, Vitalina Gryshkova, Ian Brett, C. Pecquet, Takeshi Sato, Steven O. Smith, Stefan N. Constantinescu,
Abstract Abstract 3449 Background and Aims. The thrombopoietin receptor (TpoR, c-Mpl) plays a dual role in hematopoiesis. Beside the fact that it is one of the main regulators of megacaryopoiesis and platelet formation, TpoR is also expressed in HSCs and maintains them quiescent. TpoR signals as a homodimer after ligand binding in a 1:2 (ligand to receptor) ratio. Similar to other single pass membrane receptor, it contains an extracellular ligand binding domain, one helical transmembrane domain (TMD) ...
Tópico(s): Chronic Myeloid Leukemia Treatments
2012 - Elsevier BV | Blood