Michel L Tremblay

McGill University, Montréal, Quebec, Canada

Are you Michel L Tremblay?

Claim your profile

Publications (218)1539.59 Total impact

  • Kelly A. Pike · Michel L. Tremblay
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphoid malignancies are characterized by an accumulation of genetic lesions that act co-operatively to perturb signaling pathways and alter gene expression programs. The Janus kinases (JAK)–signal transducers and activators of transcription (STATs) pathway is one such pathway that is frequently mutated in leukemia and lymphoma. In response to cytokines and growth factors, a cascade of reversible tyrosine phosphorylation events propagates the JAK–STAT pathway from the cell surface to the nucleus. Activated STAT family members then play a fundamental role in establishing the transcriptional landscape of the cell. In leukemia and lymphoma, somatic mutations have been identified in JAK and STAT family members, as well as, negative regulators of the pathway. Most recently, inactivating mutations in the protein tyrosine phosphatase (PTP) genes PTPN1 (PTP1B) and PTPN2 (TC-PTP) were sequenced in B cell lymphoma and T cell acute lymphoblastic leukemia (T-ALL) respectively. The loss of PTP1B and TC-PTP phosphatase activity is associated with an increase in cytokine sensitivity, elevated JAK–STAT signaling, and changes in gene expression. As inactivation mutations in PTPN1 and PTPN2 are restricted to distinct subsets of leukemia and lymphoma, a future challenge will be to identify in which cellular contexts do they contributing to the initiation or maintenance of leukemogenesis or lymphomagenesis. As well, the molecular mechanisms by which PTP1B and TC-PTP loss co-operates with other genetic aberrations will need to be elucidated to design more effective therapeutic strategies.
    No preview · Article · Jan 2016 · Cytokine
  • [Show abstract] [Hide abstract]
    ABSTRACT: Eph receptors and their corresponding membrane-bound ephrin ligands regulate cell positioning and establish tissue patterns during embryonic and oncogenic development. Emerging evidence suggests that assembly of polymeric Eph signalling clusters relies on cytoskeletal reorganisation and underlies regulation by protein tyrosine phosphatases (PTPs). PTP-PEST is a central regulator of actin cytoskeletal dynamics. Here we demonstrate that an N‑terminal fragment of PTP-PEST, generated through ephrinA5-triggered, spatially confined cleavage by caspase‑3, attenuates EphA3 receptor activation and its internalisation. Isolation of EphA3 receptor signalling clusters within intact plasma membrane fragments by detergent-free cell fractionation reveals that stimulation of cells with ephrin triggers effective recruitment of this catalytically active truncated form of PTP-PEST together with key cytoskeletal and focal adhesion proteins. Importantly, modulation of actin polymerisation using pharmacological and dominant-negative approaches affects EphA3 phosphorylation similar to overexpression of PTP-PEST. We conclude that PTP-PEST regulates EphA3 activation both by affecting cytoskeletal remodelling and via its direct action as PTP controlling EphA3 phosphorylation, indicating its multifaceted regulation of Eph signalling.
    No preview · Article · Dec 2015 · Journal of Cell Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: PTP1B is a master regulator in the insulin and leptin metabolic pathways. Hyper-activated PTP1B results in insulin resistance and is viewed as a key factor in the onset of type II diabetes and obesity. Moreover, inhibition of PTP1B expression in cancer cells dramatically inhibits cell growth in vitro and in vivo. Herein, we report the computationally guided optimization of a salicylic acid-based PTP1B inhibitor 6, identifying new and more potent bidentate PTP1B inhibitors, such as 20h, which exhibited a > 4-fold improvement in activity. In CHO-IR cells, 20f, 20h, and 20j suppressed PTP1B activity and restored insulin receptor phosphorylation levels. Notably, 20f, which displayed a 5-fold selectivity for PTP1B over the closely related PTPσ protein, showed no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain. Finally, 20i and 20j displayed nanomolar inhibition of PTPσ, representing interesting lead compounds for further investigation.
    No preview · Article · Sep 2015 · ACS Medicinal Chemistry Letters

  • No preview · Article · Sep 2015 · Experimental Hematology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS(-) pDCs produced IFN-α. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line. Similarly, murine Ptprs and the homologous receptor phosphatase Ptprf were specifically co-expressed in murine pDCs. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background were associated with enhanced IFN response of pDCs, leukocyte infiltration in the intestine and mild colitis. Thus, PTPRS represents an evolutionarily conserved pDC-specific inhibitory receptor, and is required to prevent spontaneous IFN production and immune-mediated intestinal inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Immunity
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · May 2015 · Science translational medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM) was induced in wild-type (WT) and PTP1B-deficient mice (KO) with streptozotocin (STZ) injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384±20 vs. Ko: 432±29 mg/dL), cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice.
    Full-text · Article · May 2015 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most of our knowledge on PTPs is derived from human pathologies and mouse knockout models. These models largely correlate well with human disease phenotypes, but can be ambiguous due to compensatory mechanisms introduced by paralogous genes. Here we present the analysis of the PTP complement of the fruit fly and the complementary view that PTP studies in Drosophila will accelerate our understanding of PTPs in physiological and pathological conditions. With only 44 PTP genes, Drosophila represents a streamlined version of the human complement. Our integrated analysis places the Drosophila PTPs into evolutionary and functional contexts, thereby providing a platform for the exploitation of the fly for PTP research and the transfer of knowledge onto other model systems. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Mar 2015 · FEBS Letters
  • [Show abstract] [Hide abstract]
    ABSTRACT: The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.Oncogene advance online publication, 17 March 2014; doi:10.1038/onc.2014.33.
    No preview · Article · Feb 2015 · Oncogene
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein, molecular chaperone, and a component of the translocon. We discovered a novel interaction between the calnexin cytoplasmic domain and UBC9, a SUMOylation E2 ligase, which modified the calnexin cytoplasmic domain by the addition of SUMO. We demonstrated that calnexin's interaction with the SUMOylation machinery modulates an interaction with protein tyrosine phosphatase 1B (PTP1B), an ER-associated protein tyrosine phosphatase involved in the negative regulation of insulin and leptin signaling. We showed that calnexin and PTP1B form UBC9-dependent complexes, revealing a previously unrecognized contribution of calnexin to the retention of PTP1B at the ER membrane. This work shows that the SUMOylation machinery links two ER proteins from divergent pathways to potentially affect cellular protein quality control and energy metabolism. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Full-text · Article · Jan 2015 · Journal of Biological Chemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims/hypothesis: Obesity is a global epidemic resulting from increased energy intake, which alters energy homeostasis and results in an imbalance in fat storage and breakdown. G0/G1 switch gene 2 (G0s2) has been recently characterised in vitro as an inhibitor of adipose triglyceride lipase (ATGL), the rate-limiting step in fat catabolism. In the current study we aim to functionally characterise G0s2 within the physiological context of a mouse model. Methods: We generated a mouse model in which G0s2 was deleted. The homozygous G0s2 knockout (G0s2 (-/-)) mice were studied over a period of 22 weeks. Metabolic variables were measured including body weight and body composition, food intake, glucose and insulin tolerance tests, energy metabolism and thermogenesis. Results: We report that G0s2 inhibits ATGL and regulates lipolysis and energy metabolism in vivo. G0s2 (-/-) mice are lean, resistant to weight gain induced by a high-fat diet and are glucose tolerant and insulin sensitive. The white adipose tissue of G0s2 (-/-) mice has enhanced lipase activity and adipocytes showed enhanced stimulated lipolysis. Energy metabolism in the G0s2 (-/-) mice is shifted towards enhanced lipid metabolism and increased thermogenesis. G0s2 (-/-) mice showed enhanced cold tolerance and increased expression of thermoregulatory and oxidation genes within white adipose tissue, suggesting enhanced 'browning' of the white adipose tissue. Conclusions/interpretation: Our data show that G0s2 is a physiological regulator of adiposity and energy metabolism and is a potential target in the treatment of obesity and insulin resistance.
    Full-text · Article · Nov 2014 · Diabetologia

  • No preview · Article · Aug 2014 · Experimental Hematology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD) contribute to injury in renal glomerular diseases, including those mediated by complement C5b-9. In this study, we address the role of protein-tyrosine phosphatase 1B (PTP1B) in complement-mediated glomerular injury and ERAD. In glomerular epithelial cells (GEC)/podocytes and in PTP1B-deficient mouse embryonic fibroblasts exposed to complement, inhibition/deletion of PTP1B reduced ERAD, as monitored by the ERAD reporter, CD3delta. Overexpression of PTP1B produced an effect similar to PTP1B deficiency on ERAD in complement-treated GEC. Complement-mediated cytotoxicity was reduced after PTP1B overexpression, and tended to be reduced after PTP1B inhibition. PTP1B enhanced the induction of certain ERAD components via the inositol requiring-1alpha branch of the UPR. PTP1B knockout mice with anti-glomerular basement membrane glomerulonephritis had decreased proteinuria, and showed less podocyte loss and ER dysfunction, compared to wild type littermates. These results imply that endogenous levels of PTP1B are tightly regulated, and both overexpression and inhibition can affect ERAD. The cytoprotective effects of PTP1B deletion in cultured cells and in anti-GBM nephritis suggest that PTP1B may potentially be a therapeutic target in complement-mediated diseases.
    Full-text · Article · Jul 2014 · American journal of physiology. Renal physiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood and urine. In addition, some cblC patients have structural abnormalities, including congenital heart defects. Mmachc is conserved in the mouse and shows tissue and stage-specific expression pattern in midgestation stage embryos. To create a mouse model of cblC we generated a line of mice with a gene-trap insertion in intron 1 of the Mmachc gene, (MmachcGt(AZ0348)Wtsi). Heterozygous mice show a 50% reduction of MMACHC protein, and have significantly higher levels of homocysteine and methylmalonic acid in their blood. The MmachcGt allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous MmachcGt embryos were not found after embryonic day 3.5 and these embryos were unable to generate giant cells in outgrowth assays. Our findings confirm that cblC is modeled in mice with reduced levels of Mmachc and suggest an early requirement for Mmachc in mouse development.
    Preview · Article · Jul 2014 · Molecular Genetics and Metabolism
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Both pro- and anti-inflammatory cytokines activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; however, they elicit distinct transcriptional programs. Posttranslational modifications of STAT proteins, such as tyrosine phosphorylation, are critical to ensure the differential expression of STAT target genes. Although JAK-STAT signaling is dependent on reversible tyrosine phosphorylation, whether phosphatases contribute to the specificity of STAT-dependent gene expression is unclear. We examined the role of protein tyrosine phosphatase 1B (PTP1B) in regulating the interleukin-10 (IL-10)-dependent, STAT3-mediated anti-inflammatory response. We found that IL-10-dependent STAT3 phosphorylation and anti-inflammatory gene expression were enhanced in macrophages from PTP1B(-/-) mice compared to those in macrophages from wild-type mice. Consistent with this finding, the IL-10-dependent suppression of lipopolysaccharide-induced macrophage activation was increased in PTP1B(-/-) macrophages compared to that in wild-type macrophages, as was the IL-10-dependent increase in the cell surface expression of the anti-inflammatory cytokine receptor IL-4Rα. Furthermore, RNA sequencing revealed the expression of genes encoding proinflammatory factors in IL-10-treated PTP1B(-/-) macrophages, which correlated with increased phosphorylation of STAT1, which is not normally highly activated in response to IL-10. These findings identify PTP1B as a central regulator of IL-10R-STAT3 and IL-10R-STAT1 signaling, and demonstrate that phosphatases can tailor the quantitative and qualitative properties of cytokine-induced transcriptional responses.
    Full-text · Article · May 2014 · Science Signaling
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. One compound 211 exhibited CD45 IC50 200 nM and had >100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site directed mutagenesis. Compound 211 has a non-competitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck pY-505 versus preventing dephosphorylation of Lck pY-394. In cultured primary T cells, 211 prevents T-cell receptor-mediated activation of Lck, Zap-70 and MAPK, and IL-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.
    Preview · Article · Jan 2014 · Molecular pharmacology
  • Matthew Feldhammer · Michel L Tremblay

    No preview · Article · Jan 2014 · Methods
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 20q13 chromosomal region has been previously identified as the hereditary prostate cancer genetic-susceptibility locus on chromosome 20 (HPC20). In this study, the 20q13 region was shown to be frequently co-amplified with the androgen receptor (AR) in metastatic prostate cancer. Furthermore, the AR signaling axis, which plays an essential role in the pathogenesis of prostate cancer, was demonstrated to be central to the regulation of the 20q13 common amplified region (CAR). High-resolution mapping analyses revealed hot spots of AR recruitment to response elements in the vicinity of most genes located on the 20q13 CAR. Moreover, amplification of AR significantly co-occurred with CAR amplification on 20q13 and it was confirmed that the majority of AR-bound genes on the 20q13 CAR were indeed regulated by androgens. These data reveal that amplification of the AR is tightly linked to amplification of the AR-regulated CAR region on 20q13. These results suggest that the cross-talk between gene amplification and gene transcription is an important step in the development of castration-resistant metastatic disease. *MLT and LCT are co-corresponding authors
    Full-text · Article · Dec 2013 · Molecular Cancer Research

  • No preview · Conference Paper · Dec 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: For years, the two main isoforms of PTPN2 have been an interesting yet academic topic of debate for researchers working on this phosphatase. In recent years, several studies were published in which these isoforms were attributed specific functions. Most importantly, differences in their stoichiometry have been reported to be associated with certain diseases such as inflammatory bowel diseases (IBDs). Hence, understanding the evolutionary ontogeny of the main transcripts and the physiological consequences of their expression have now become clinically relevant issues. Herein we describe the genomic controls placed upon PTPN2, the identified splice variants, the encoded PTPN2 proteins, and both the known and putative post-translational modifications that have been reported. Moreover, we examine the expression of PTPN2 isoforms in specific tissues as well as in a disease setting. PTPN2 is an important negative regulator of inflammation. Therefore, the following protocols are effective approaches for its adequate monitoring in inflammatory diseases' progression and outcome.
    No preview · Article · Aug 2013 · Methods

Publication Stats

13k Citations
1,539.59 Total Impact Points

Institutions

  • 1994-2015
    • McGill University
      • • Department of Biochemistry
      • • Division of Experimental Medicine
      • • McGill Cancer Center
      Montréal, Quebec, Canada
  • 2008
    • Université de Montréal
      Montréal, Quebec, Canada
  • 2007
    • Academia Sinica
      • Institute of Biological Chemistry
      T’ai-pei, Taipei, Taiwan
  • 2006
    • Fred Hutchinson Cancer Research Center
      • Division of Basic Sciences
      Seattle, Washington, United States
  • 2005
    • Monash University (Australia)
      • Department of Biochemistry and Molecular Biology
      Melbourne, Victoria, Australia
  • 2004
    • McGill University Health Centre
      Montréal, Quebec, Canada
    • Friedrich-Schiller-University Jena
      • Institute of Molecular Cell Biology
      Jena, Thuringia, Germany
    • Instituto de Investigación Clínica de Occidente
      Zapopan, Jalisco, Mexico
  • 2003
    • Cornell University
      • Department of Animal Science
      Ithaca, New York, United States
  • 2002
    • University of Western Australia
      Perth City, Western Australia, Australia
    • University of California, Los Angeles
      • Department of Medicine
      Los Ángeles, California, United States
  • 1995
    • University of Toronto
      Toronto, Ontario, Canada
  • 1992
    • National Institutes of Health
      베서스다, Maryland, United States