Sylvain Meloche

Université de Montréal | UdeM · Institute for Research in Immunology and Cancer

ERK3/MAPK6 activates MAP kinase‐activated protein kinase (MK)‐5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac...

Cytokinesis is the last step of cell division and is regulated by the small GTPase RhoA. RhoA activity is required for all steps of cytokinesis, including prior to abscission when daughter cells are ultimately physically separated. Like germ cells in all animals, the Caenorhabditis elegans embryonic germline founder cell initiates cytokinesis but d...

Most of our understanding regarding the involvement of SRC-family tyrosine kinases in cancer has stemmed from studies focused on the prototypical SRC oncogene. However, emerging research has shed light on the important role of YES signaling in oncogenic transformation, tumor growth, metastatic progression, and resistance to various cancer therapies...

Cytokinesis is the last step of cell division and is regulated by the small GTPase RhoA. RhoA activity is required for all steps of cytokinesis, including prior to abscission when daughter cells are ultimately physically separated. Like germ cells in all animals, the C. elegans embryonic germline founder cell initiates cytokinesis but does not comp...

p21Cip1 (p21) is a universal cyclin-dependent kinase (CDK) inhibitor that halts cell proliferation and tumor growth by multiple mechanisms. The expression of p21 is often downregulated in cancer cells as a result of the loss of function of transcriptional activators, such as p53, or the increased degradation rate of the protein. To identify small m...

Identification of dominant, actionable oncogenic signaling pathways is key to guide the development of new targeted treatments for advanced-stage hepatocellular carcinoma (HCC). We have recently unveiled a novel YES-YAP/TAZ signaling axis involved in liver cancer development. Our study identifies the tyrosine kinase YES as a potential therapeutic t...

Simple Summary Patients with triple-negative breast cancer have a poor outcome owing to the clinically aggressive behavior of the disease and the lack of hormonal or targeted therapies. Identification of new actionable targets to guide the development of effective treatments remains a critical clinical need. It has been recently suggested that the...

Extracellular signal‐regulated kinase 3 (ERK3) is a poorly characterized member of the mitogen‐activated protein (MAP) kinase family. Functional analysis of the ERK3 signaling pathway has been hampered by a lack of knowledge about the substrates and downstream effectors of the kinase. Here, we used large‐scale quantitative phosphoproteomics and tar...

ERK3/MAPK6 (MAPK6 gene) along with its paralog ERK4/MAPK4 (MAPK4 gene) define a distinct subfamily of atypical mitogen-activated protein kinases (MAPKs). Much remains to be learned about the substrates and biological functions of these signaling enzymes. Interestingly, recent work has suggested that ERK4 promotes prostate cancer progression via the...

Front Cover: The cover image is based on the Research Article ERK3‐MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation by Sylvain Meloche et al., https://doi.org/10.1002/jcp.30695.

UBCH10 is an ubiquitin-conjugating enzyme (E2) of the anaphase-promoting complex E3 ligase, a key regulator of the cell cycle. The UBCH10 gene and protein are frequently upregulated in multiple solid tumors, associated with an unfavorable outcome. Accumulating evidence from studies of human cancer cell lines, mouse transgenic models, and analyses o...

The physiological functions and downstream effectors of the atypical mitogen‐activated protein kinase extracellular signal‐regulated kinase 3 (ERK3) remain to be characterized. We recently reported that mice expressing catalytically‐inactive ERK3 (Mapk6KD/KD) exhibit a reduced postnatal growth rate as compared to control mice. Here, we show that ge...

Most patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage and have few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or a dominant oncogene that can be targeted pharmacologically, unlike in other cancer types. Here, we report the identification of a previously unchar...

Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that play essential roles in transducing extracellular environmental signals into diverse cellular responses to maintain homeostasis. These pathways are classically organized into an architecture of three sequentially acting protein kinases: a MAPK kina...

The physiological functions and downstream effectors of the atypical mitogen-activated protein kinase ERK3 remain to be characterized. We recently reported that mice expressing catalytically-inactive ERK3 (Mapk6KD/KD) exhibit a reduced post-natal growth rate as compared to control mice. Here, we show that genetic inactivation of ERK3 impairs post-n...

Interleukin-17 receptor D (IL-17RD) is an evolutionarily conserved member of the IL-17 receptor family. Originally identified as a negative regulator of fibroblast growth factor (FGF) signaling under the name of Sef (Similar expression to FGF genes), IL-17RD was subsequently reported to regulate other receptor tyrosine kinase signaling pathways. In...

Interleukin-17 receptor D (IL-17RD), also known as similar expression to Fgf genes (SEF), is proposed to act as a signaling hub that negatively regulates mitogenic signaling pathways, like the ERK1/2 MAP kinase pathway, and innate immune signaling. The expression of IL-17RD is downregulated in certain solid tumors, which has led to the hypothesis t...

Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the...

The physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus ( Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturatio...

The physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation...

shRNA expression is an established technique to transiently or permanently deplete cells of a particular mRNA/protein. In functional analyses of oncogenic pathways it can thus be used as an alternative to pharmacologic inhibitors, or as a means to address otherwise undruggable targets. Here we describe and functionally validate a simple reiterative...

Review on MAPK6, with data on DNA, on the protein encoded, and where the gene is implicated. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology.

Mouse embryonic stem (ES) cells have proven to be invaluable research tools for dissecting the role of signaling pathways in embryonic development, adult physiology, and various diseases. ES cells are amenable to genetic manipulation by classical gene targeting via homologous recombination or by genome editing technologies. These cells can be used...

Recent work has suggested that the activity of extracellular signal-regulated kinase (ERK) 1/2 is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and non-characteri...

The RAS-RAF-MEK-ERK pathway has been intensively studied in oncology with RAS known to be mutated in ~30% of all human cancers. The recent emergence of ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding of ERK1/2 behaviour following small molecule inhibition. Although fluorescent fusion proteins and fluorescen...

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein (MAP) kinase whose regulatory mechanisms and biological functions remain superficially understood. Contrary to most protein kinases, ERK3 is a highly unstable protein that is subject to dynamic regulation by the ubiquitin-proteasome system. However, the effector...

The protein kinases ERK1 and ERK2 are the effector components of the prototypical ERK1/2 mitogen-activated protein (MAP) kinase pathway. This signaling pathway regulates cell proliferation, differentiation and survival, and is essential for embryonic development and cellular homeostasis. ERK1 and ERK2 homologs share similar biochemical properties b...

Aneuploidy is a common feature of human solid tumors and is often associated with poor prognosis. There is growing evidence that oncogenic signaling pathways, which are universally dysregulated in cancer, contribute to the promotion of aneuploidy. However, the mechanisms connecting signaling pathways to the execution of mitosis and cytokinesis are...

The Ras-related (R-Ras) isoforms TC21, R-Ras and M-Ras are members of the Ras superfamily of small GTPases. R-Ras family proteins are frequently overexpressed in human cancers, and expression of activated mutants of these GTPases is sufficient to induce cell transformation. Unlike Ras, few activating mutations of R-Ras proteins have been reported i...

Background: Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully...

In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which sig...

Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with...

ERK1 and ERK2 are the effector kinases of the ERK1/2 MAP-kinase signaling pathway, which plays a central role in transducing signals controlling cell proliferation, differentiation, and survival. Deregulated activity of the ERK1/2 pathway is linked to a group of developmental syndromes and contributes to the pathogenesis of various human diseases....

It has been previously shown that the polycomb protein BMI1 and E4F1 interact physically and genetically in the hematopoietic system. Here, we report that E4f1 is essential for hematopoietic cell function and survival. E4f1 deletion induces acute bone marrow failure characterized by apoptosis of progenitors while stem cells are preserved. E4f1-defi...

ERK3 is an atypical member of the MAPK family. We have previously shown that ERK3 is expressed during thymocyte differentiation and that its expression is induced in mature peripheral T cells following activation of ERK1/2 by T cell receptor (TCR) signalling. Herein, we have investigated whether ERK3 expression is required for proper T cell selecti...

Inhibition or allosteric modulation of mitogen-activated protein kinase kinases MEK1 and MEK2 (MEK1/2) represent a promising strategy for the discovery of new specific anticancer agents. In this paper, structure-based design, beginning from the lead compound PD98059, was used to study potential structural modifications on the chromone structure in...

Multipotent long-term repopulating hematopoietic stem cells (LT-HSCs) can self-renew or differentiate into the less primitive short-term repopulating stem cells (ST-HSCs), which themselves produce progenitors that ensure the daily supply of all essential blood components. The Polycomb group (PcG) protein BMI1 is essential for the activity of both H...

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family whose function is largely unknown. Given the central role of MAPKs in T cell development, we hypothesized that ERK3 may regulate thymocyte development. Here we have shown that ERK3 deficiency leads to a 50% reduction in CD4+ CD...

BACKGROUND Respiratory distress syndrome (RDS) persists as a prevalent cause of infant morbidity and mortality. We have previously demonstrated that deletion of Erk3 results in pulmonary immaturity and neonatal lethality. Using RNA-Seq, we identified corticotrophin releasing hormone (CRH) and surfactant protein B (SFTPB) as potential molecular medi...

The classical mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 are activated upon stimulation of cells with a broad range of extracellular signals (including antigens) allowing cellular responses to occur. ERK3 is an atypical member of the MAPK family with highest homology to ERK1/2. Therefore, we evaluated the role of ERK3 in mature T cell...

The extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2) cascade regulates a variety of cellular processes by phosphorylating multiple target proteins. The outcome of its activation ranges from stimulation of cell survival and proliferation to triggering tumor suppressor responses such as cell differentiation, cell senescence, and apoptosis...

The ERK1/2 MAP kinase pathway is an evolutionarily conserved signaling module that controls many fundamental physiological processes. Deregulated activity of ERK1/2 MAP kinases is associated with developmental syndromes and several human diseases. Despite the importance of this pathway, a comprehensive picture of the natural substrate repertoire an...

Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (Nras(G12D/+)) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of Nras(G...

Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. In primary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAP kinase signaling by genetic inactivation of Erk2, RNAi-mediated knockdown of ERK...

Purpose Since the initial observations of Liggins demonstrating dexamethasone-induced inflation of fetal lungs, antenatal glucocorticoids have become the mainstay clinical management for the promotion of fetal lung maturation. The molecular mechanisms by which this prevalent therapy manifests functionally are poorly understood. We previously repo...

The Ras/mitogen-activated protein kinase (MAPK) signalling cascade regulates various biological functions, including cell growth, proliferation and survival. As such, this pathway is often deregulated in cancer, including melanomas, which frequently harbour activating mutations in the NRAS and BRAF oncogenes. Hyperactive MAPK signalling is known to...

We recently generated 2 phenotypically similar Hoxa9+Meis1 overexpressing acute myeloid leukemias that differ by their in vivo biologic behavior. The first leukemia, named FLA2, shows a high frequency of leukemia stem cells (LSCs; 1 in 1.4 cells), whereas the second, FLB1, is more typical with a frequency of LSCs in the range of 1 per several hundr...

Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 inter...

L'angiotensine II est une hormone peptidique qui exerce une multitude d'actions biologiques au niveau du systeme cardio-vasculaire, du rein et du systeme nerveux central. Les effets de l'hormone sont relayes par deux sous-types de recepteurs, AT 1 et AT 2 , appartenant a la famille des recepteurs a sept domaines transmembranaires. Outre ses effets...

Protein synthesis is energetically costly and is tightly regulated by evolutionarily conserved mechanisms. Under restrictive growth conditions and in response to various stresses, such as DNA damage, cells inhibit protein synthesis to redirect available adenosine triphosphate to more essential processes. Conversely, proliferating cells, such as can...

Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 5 (MK5) deficiency is associated with reduced extracellular signal-regulated kinase 3 (ERK3) (mitogen-activated protein kinase 6) levels, hence we utilized the MK5 knockout mouse model to analyze the physiological functions of the ERK3/MK5 signaling module. MK5-deficient mice displa...

Subcellular trafficking of key oncogenic signal pathway components is likely to be crucial for neoplastic transformation, but little is known about how such trafficking processes are spatially controlled. In this study, we show how Ras activation causes aberrant nuclear localization of phosphorylated mitogen-activated protein (MAP)/extracellular si...

Despite extensive clinical use, the mechanisms by which in utero glucocorticoids promote fetal lung maturity are not well understood. We hypothesized that whole transcriptome shotgun sequencing (RNA-Seq) in biologically relevant models would reveal potential gene pathways by which glucocorticoids antenatally function. We previously reported that in...

Novel and improved computational tools are required to transform large-scale proteomics data into valuable information of biological relevance. To this end, we developed ProteoConnections, a bioinformatics platform tailored to address the pressing needs of proteomics analyses. The primary focus of this platform is to organize peptide and protein id...

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 th...

An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, whereas volume overload or exercise results in eccentric growth characterized by cellular elongation and addition of sarcomeres in series. The signaling pathways that control eccentric versus concentric heart growth are no...

The small ubiquitin-related modifier (SUMO) is a small group of proteins that are reversibly attached to protein substrates to modify their functions. The large scale identification of protein SUMOylation and their modification sites in mammalian cells represents a significant challenge because of the relatively small number of in vivo substrates a...

Classical mitogen-activated protein (MAP) kinases are activated by dual phosphorylation of the Thr-Xxx-Tyr motif in their activation loop, which is catalyzed by members of the MAP kinase kinase family. The atypical MAP kinases extracellular signal-regulated kinase 3 (ERK3) and ERK4 contain a single phospho-acceptor site in this segment and are not...

Classical mitogen-activated protein (MAP) kinases are activated by dual phosphorylation of the Thr-Xxx-Tyr motif in their activation loop, which is catalyzed by members of the MAP kinase kinase family. The atypical MAP kinases extracellular signal-regulated kinase 3 (ERK3) and ERK4 contain a single phospho-acceptor site in this segment and are not...

The extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase module is a conserved signaling pathway that plays a major role in the control of cell proliferation, survival and differentiation. This pathway is typically turned on by engagement of growth factor receptors, which leads to the activation of the small GTPase...

Erk4 and Erk3 are atypical members of the mitogen-activated protein (MAP) kinase family. The high sequence identity of Erk4 and Erk3 proteins and the similar organization of their genes imply that the two protein kinases are paralogs. Recently, we have shown that Erk3 function is essential for neonatal survival and critical for the establishment of...

The extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase signaling pathway plays an important role in the proliferative response of mammalian cells to mitogens. However, the individual contribution of the isoforms ERK1 and ERK2 to cell proliferation control is unclear. The two ERK isoforms have similar bioch...

Skp2 is the substrate binding subunit of the SCF(Skp2) ubiquitin ligase, which plays a key role in the regulation of cell cycle progression. The activity of Skp2 is regulated by the APC(Cdh1), which targets Skp2 for degradation in early G(1) and prevent premature S phase entry. Overexpression of Skp2 leads to dysregulation of the cell cycle and is...

ERK3 (extracellular-signal-regulated kinase 3) is an atypical MAPK (mitogen-activated protein kinase) that is suggested to play a role in cell-cycle progression and cellular differentiation. However, it is not known whether the function of ERK3 is regulated during the cell cycle. In the present paper, we report that ERK3 is stoichiometrically hyper...

The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF...

Extracellular signal-regulated kinase 3 (Erk3) is an atypical member of the mitogen-activated protein (MAP) kinase family. No function has yet been ascribed to this MAP kinase. Here we show that targeted disruption of the Mapk6 gene (encoding Erk3) leads to intrauterine growth restriction, associated with marked pulmonary hypoplasia, and early neon...

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate...

Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER) stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR). The UPR regulates the two key processes that control major histocompatibility com...

The mouse represents the model of choice to study the biological function of mammalian genes through mutation of its genome. However, the biggest challenge of mouse geneticists remains the phenotypic analysis of mouse mutants. A survey of mouse mutant databases reveals a surprisingly high number of gene mutations leading to neonatal death. These ge...

Mitogen-activated protein (MAP) kinases are typical examples of protein kinases whose enzymatic activity is mainly controlled by activation loop phosphorylation. The classical MAP kinases ERK1/ERK2, JNK, p38 and ERK5 all contain the conserved Thr-Xxx-Tyr motif in their activation loop that is dually phosphorylated by members of the MAP kinase kinas...

The Ras-dependent ERK1/2 MAP kinase signaling pathway plays a central role in cell proliferation control and is frequently activated in human colorectal cancer. Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy. However, the exact contribution of MEK1 and MEK2 to th...

Sulfation and phosphorylation are post-translational modifications imparting an isobaric 80-Da addition on the side chain of serine, threonine, or tyrosine residues. These two post-translational modifications are often difficult to distinguish because of their similar MS fragmentation patterns. Targeted MS identification of these modifications in s...

Over the past four years, the field of the innate immune response has been highly influenced by the discovery of the IkappaB kinase (IKK)-related kinases, TANK Binding Kinase 1 (TBK1) and IKKi, which regulate the activity of interferon regulatory factor (IRF)-3/IRF-7 and NF-kappaB transcription factors. More recently, additional essential component...

Eukaryotic initiation factor 4E (eIF4E) promotes cellular proliferation and can rescue cells from apoptotic stimuli such as serum starvation. However, the mechanisms underlying apoptotic rescue are not well understood. In this study, we demonstrate that eIF4E overexpression leads to enhanced survival signaling through Akt and that eIF4E requires Ak...

The p27(Kip1) ubiquitin ligase receptor Skp2 is often overexpressed in human tumours and displays oncogenic properties. The activity of SCF(Skp2) is regulated by the APC(Cdh1), which targets Skp2 for degradation. Here we show that Skp2 phosphorylation on Ser64/Ser72 positively regulates its function in vivo. Phosphorylation of Ser64, and to a lesse...

The IkappaB kinase-related kinases, TBK1 and IKKi, were recently shown to be responsible for the C-terminal phosphorylation of IRF-3. However, the identity of the phosphoacceptor site(s) targeted by these two kinases remains unclear. Using a biological assay based on the IRF-3-mediated production of antiviral cytokines, we demonstrate here that all...

MAPK signaling pathways function as critical regulators of cellular differentiation, proliferation, stress responsiveness, and apoptosis. One branch of the MAPK signaling pathway that culminates in ERK1/2 activation is hypothesized to regulate the growth and adaptation of the heart to both physiologic and pathologic stimuli, given its known activat...

Pluripotent embryonic stem (ES) cells must select between alternative fates of self-replication and lineage commitment during continuous proliferation. Here, we delineate the role of autocrine production of fibroblast growth factor 4 (Fgf4) and associated activation of the Erk1/2 (Mapk3/1) signalling cascade. Fgf4 is the major stimulus activating E...

Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that play a central role in transducing extracellular cues into a variety of intracellular responses ranging from lineage specification to cell division and adaptation. Fourteen MAP kinase genes have been identified in the human genome, which define 7 distinct MAP kina...