Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Catherine H. Regnier is active.

Publication


Featured researches published by Catherine H. Regnier.


Journal of Experimental Medicine | 2012

Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Oliver Weigert; Andrew A. Lane; Liat Bird; Nadja Kopp; Bjoern Chapuy; Diederik van Bodegom; Angela V. Toms; Sachie Marubayashi; Amanda L. Christie; Michael R. McKeown; Ronald M. Paranal; James E. Bradner; Akinori Yoda; Christoph Gaul; Eric Vangrevelinghe; Vincent Romanet; Masato Murakami; Ralph Tiedt; Nicolas Ebel; Emeline Evrot; Alain De Pover; Catherine H. Regnier; Dirk Erdmann; Francesco Hofmann; Michael J. Eck; Stephen E. Sallan; Ross L. Levine; Andrew L. Kung; Fabienne Baffert; Thomas Radimerski

Hsp90 inhibition in B cell acute lymphoblastic leukemia overcomes resistance to JAK2 inhibitors.


Molecular Cancer Therapeutics | 2010

Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Fabienne Baffert; Catherine H. Regnier; Alain De Pover; Carole Pissot-Soldermann; Gisele A. Tavares; Francesca Blasco; Josef Brueggen; Patrick Chène; Peter Drueckes; Dirk Erdmann; Pascal Furet; Marc Gerspacher; Marc Lang; David Ledieu; Lynda Nolan; Stephan Ruetz; Joerg Trappe; Eric Vangrevelinghe; Markus Wartmann; Lorenza Wyder; Francesco Hofmann; Thomas Radimerski

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945–55. ©2010 AACR.


Cancer Discovery | 2012

Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Rita Andraos; Zhiyan Qian; Débora Bonenfant; Joëlle Rubert; Eric Vangrevelinghe; Clemens Scheufler; Fanny Marque; Catherine H. Regnier; Alain De Pover; Hugues Ryckelynck; Neha Bhagwat; Priya Koppikar; Aviva Goel; Lorenza Wyder; Gisele Tavares; Fabienne Baffert; Carole Pissot-Soldermann; Paul W. Manley; Christoph Gaul; Hans Voshol; Ross L. Levine; William R. Sellers; Francesco Hofmann; Thomas Radimerski

Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.


Nature Communications | 2015

The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling

Theo Klein; Shan-Yu Fung; Florian Renner; Michael Blank; Antoine Dufour; Sohyeong Kang; Madison Bolger-Munro; Joshua Scurll; John J. Priatel; Patrick Schweigler; Samu Melkko; Michael R. Gold; Rosa Viner; Catherine H. Regnier; Stuart E. Turvey; Christopher M. Overall

Antigen receptor signalling activates the canonical NF-κB pathway via the CARD11/BCL10/MALT1 (CBM) signalosome involving key, yet ill-defined roles for linear ubiquitination. The paracaspase MALT1 cleaves and removes negative checkpoint proteins, amplifying lymphocyte responses in NF-κB activation and in B-cell lymphoma subtypes. To identify new human MALT1 substrates, we compare B cells from the only known living MALT1mut/mut patient with healthy MALT1+/mut family members using 10-plex Tandem Mass Tag TAILS N-terminal peptide proteomics. We identify HOIL1 of the linear ubiquitin chain assembly complex as a novel MALT1 substrate. We show linear ubiquitination at B-cell receptor microclusters and signalosomes. Late in the NF-κB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-κB activation and preventing reactivation. By regulating linear ubiquitination, MALT1 is both a positive and negative pleiotropic regulator of the human canonical NF-κB pathway—first promoting activation via the CBM—then triggering HOIL1-dependent negative-feedback termination, preventing reactivation.


Journal of Immunology | 2015

Deficiency of MALT1 Paracaspase Activity Results in Unbalanced Regulatory and Effector T and B Cell Responses Leading to Multiorgan Inflammation

Frédéric Bornancin; Florian Renner; Ratiba Touil; Heiko Sic; Yeter Kolb; Ismahane Touil-Allaoui; James Rush; Paul Smith; Marc Bigaud; Ursula Junker-Walker; Christoph Burkhart; Janet Dawson; Satoru Niwa; Andreas Katopodis; Barbara Nuesslein-Hildesheim; Gisbert Weckbecker; Gerhard Zenke; Bernd Kinzel; Elisabetta Traggiai; Dirk Brenner; Anne Brüstle; Michael St. Paul; Natasa Zamurovic; Kathleen McCoy; Antonius Rolink; Catherine H. Regnier; Tak W. Mak; Pamela S. Ohashi; Dhavalkumar D. Patel; Thomas Calzascia

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1PD/PD) and compared their phenotype with that of MALT1 knockout animals (Malt1−/−). Malt1PD/PD mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10–producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1−/− animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1PD/PD mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1PD/PD animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1PD/PD animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.


Bioorganic & Medicinal Chemistry Letters | 2010

Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors.

Carole Pissot-Soldermann; Marc Gerspacher; Pascal Furet; Christoph Gaul; Philipp Holzer; Clive Mccarthy; Thomas Radimerski; Catherine H. Regnier; Fabienne Baffert; Peter Drueckes; Gisele Tavares; Eric Vangrevelinghe; Francesca Blasco; Giorgio Ottaviani; Flavio Ossola; Julien Scesa; Janitha Reetz

We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokinetic properties suitable for in vivo efficacy evaluation.


Bioorganic & Medicinal Chemistry Letters | 2010

2-Amino-aryl-7-aryl-benzoxazoles as potent, selective and orally available JAK2 inhibitors

Marc Gerspacher; Pascal Furet; Carole Pissot-Soldermann; Christoph Gaul; Philipp Holzer; Eric Vangrevelinghe; Marc Lang; Dirk Erdmann; Thomas Radimerski; Catherine H. Regnier; Patrick Chène; Alain De Pover; Francesco Hofmann; Fabienne Baffert; Thomas Buhl; Reiner Aichholz; Francesca Blasco; Ralf Endres; Jörg Trappe; Peter Drueckes

A series of novel benzoxazole derivatives has been designed and shown to exhibit attractive JAK2 inhibitory profiles in biochemical and cellular assays, capable of delivering compounds with favorable PK properties in rats. Synthesis and structure-activity relationship data are also provided.


Science Translational Medicine | 2016

Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2

Natalia Arenas-Ramirez; Chao Zou; Simone Popp; Daniel Zingg; Barbara Brannetti; Emmanuelle Wirth; Thomas Calzascia; Jiri Kovarik; Lukas Sommer; Gerhard Zenke; Janine Woytschak; Catherine H. Regnier; Andreas Katopodis; Onur Boyman

An antibody to human IL-2 phenocopies CD25 and improves IL-2–based cancer immunotherapy. Running interference Interleukin-2 (IL-2) binds to receptors on multiple different types of T cells. CD8 T cells, which can kill tumor cells, have IL-2 receptors with two subunits. When IL-2 binds to these, it promotes the T cells’ activation. In contrast, regulatory T cells dampen the antitumor immune response, and they express a different type of IL-2 receptor, which contains CD25 in addition to the other two subunits. CD25 binds IL-2 tightly but does not signal. To address this, Arenas-Ramirez et al. developed an anti–IL-2 antibody that can block CD25, such that delivering the antibody together with IL-2 allows IL-2 to bind specifically to the two-subunit IL-2 receptors and promote an antitumor immune response without interference from regulatory T cells. Interleukin-2 (IL-2) immunotherapy is an attractive approach in treating advanced cancer. However, by binding to its IL-2 receptor α (CD25) subunit, IL-2 exerts unwanted effects, including stimulation of immunosuppressive regulatory T cells (Tregs) and contribution to vascular leak syndrome. We used a rational approach to develop a monoclonal antibody to human IL-2, termed NARA1, which acts as a high-affinity CD25 mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2–NARA1 complex revealed that NARA1 occupies the CD25 epitope of IL-2 and precisely overlaps with CD25. Association of NARA1 with IL-2 occurs with 10-fold higher affinity compared to CD25 and forms IL-2/NARA1 complexes, which, in vivo, preferentially stimulate CD8+ T cells while disfavoring CD25+ Tregs and improving the benefit–to–adverse effect ratio of IL-2. In two transplantable and one spontaneous metastatic melanoma model, IL-2/NARA1 complex immunotherapy resulted in efficient expansion of tumor-specific and polyclonal CD8+ T cells. These CD8+ T cells showed robust interferon-γ production and expressed low levels of exhaustion markers programmed cell death protein-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin domain-3. These effects resulted in potent anticancer immune responses and prolonged survival in the tumor models. Collectively, our data demonstrate that NARA1 acts as a CD25-mimobody that confers selectivity and increased potency to IL-2 and warrant further assessment of NARA1 as a therapeutic.


Immunology and Cell Biology | 2018

The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition

Maureen Bardet; Adeline Unterreiner; Claire Malinverni; Frédérique Lafossas; Corinne Vedrine; Danielle Boesch; Yeter Kolb; Daniel Kaiser; Anton Glück; Martin A. Schneider; Andreas Katopodis; Martin Renatus; Oliver Simic; Achim Schlapbach; Jean Quancard; Catherine H. Regnier; Guido Bold; Carole Pissot-Soldermann; José M. Carballido; Jiri Kovarik; Thomas Calzascia; Frédéric Bornancin

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T‐cell activation and fate after engagement of the T‐cell receptor pathway. We show that MLT‐827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T‐cell activation, in contrast to the pan‐protein kinase C inhibitor AEB071. However, MLT‐827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL‐2 production as well as reduced expression of the IL‐2 receptor alpha subunit (CD25), resulting from defective canonical NF‐κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT‐827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T‐cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion.


PLOS ONE | 2017

Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation

Stefanie Ginster; Maureen Bardet; Adeline Unterreiner; Claire Malinverni; Florian Renner; Stephen Lam; Felix Freuler; Bertran Gerrits; Johannes Voshol; Thomas Calzascia; Catherine H. Regnier; Martin Renatus; Rainer Nikolay; Laura Israël; Frédéric Bornancin

The paracaspase MALT1 has arginine-directed proteolytic activity triggered by engagement of immune receptors. Recruitment of MALT1 into activation complexes is required for MALT1 proteolytic function. Here, co-expression of MALT1 in HEK293 cells, either with activated CARD11 and BCL10 or with TRAF6, was used to explore the mechanism of MALT1 activation at the molecular level. This work identified a prominent self-cleavage site of MALT1 isoform A (MALT1A) at R781 (R770 in MALT1B) and revealed that TRAF6 can activate MALT1 independently of the CBM. Intramolecular cleavage at R781/R770 removes a C-terminal TRAF6-binding site in both MALT1 isoforms, leaving MALT1B devoid of the two key interaction sites with TRAF6. A previously identified auto-proteolysis site of MALT1 at R149 leads to deletion of the death-domain, thereby abolishing interaction with BCL10. By using MALT1 isoforms and cleaved fragments thereof, as well as TRAF6 WT and mutant forms, this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover. The MALT1 fragment generated by N-terminal self-cleavage at R149 was labile and displayed enhanced signaling properties that required an intact K644 residue, previously shown to be a site for mono-ubiquitination of MALT1. Conversely, C-terminal self-cleavage at R781/R770 hampered the ability for self-cleavage at R149 and stabilized MALT1 by hindering interaction with TRAF6. C-terminal self-cleavage had limited impact on MALT1A but severely reduced MALT1B proteolytic and signaling functions. It also abrogated NF-κB activation by N-terminally cleaved MALT1A. Altogether, this study provides further insights into mechanisms that regulate the scaffolding and activation cycle of MALT1. It also emphasizes the reduced functional capacity of MALT1B as compared to MALT1A.

Collaboration


Dive into the Catherine H. Regnier's collaboration.

Researchain Logo
Decentralizing Knowledge