Roger J Davis

University of Massachusetts Medical School, Worcester, Massachusetts, United States

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Publications (188)1902.43 Total impact

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    ABSTRACT: Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wld(s) protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell. 01/2015; 160(1-2):161-176.
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    ABSTRACT: An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (1). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α mitogen activated protein kinase (MAPK) in ectodermal appendages using K14-cre mice (p38αK14 mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel due to defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and β4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 11/2014; · 4.60 Impact Factor
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    ABSTRACT: Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1), however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both fast-velocity (∼2.7 μm/s) and high-frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function located in the central region of JIP1b that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11-amino-acid C-terminal (C11) region with the tetratrico-peptide repeat of KLC1. High-frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast-velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr(668), a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons is mediated by novel roles of JIP1b.
    Molecular Biology of the Cell 08/2014; · 4.55 Impact Factor
  • Guadalupe Sabio, Roger J. Davis
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    ABSTRACT: The binding of tumour necrosis factor α (TNFα) to cell surface receptors engages multiple signal transduction pathways, including three groups of mitogen-activated protein (MAP) kinases: extracellular-signal-regulated kinases (ERKs); the cJun NH2-terminal kinases (JNKs); and the p38 MAP kinases. These MAP kinase signalling pathways induce a secondary response by increasing the expression of several inflammatory cytokines (including TNFα) that contribute to the biological activity of TNFα. MAP kinases therefore function both upstream and down-stream of signalling by TNFα receptors. Here we review mechanisms that mediate these actions of MAP kinases during the response to TNFα.
    Seminars in Immunology 06/2014; · 6.12 Impact Factor
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    ABSTRACT: The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
    Cell Reports 04/2014; · 7.21 Impact Factor
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    ABSTRACT: The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of KrasG12D with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of KrasG12D-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonising the metaplastic conversion of acinar cells towards a ductal fate capable of responding to oncogenic stimulation.
    Cancer Research 04/2014; · 9.28 Impact Factor
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    ABSTRACT: The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.
    Cell metabolism. 01/2014;
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    ABSTRACT: The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet-induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway.
    Genes & development 11/2013; 27(21):2345-55. · 12.64 Impact Factor
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    ABSTRACT: Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-α and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-α-induced insulin resistance, and we found that C/EPBβ is a potential key regulator of adipose insulin resistance.
    Cell Reports 10/2013; · 7.21 Impact Factor
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    ABSTRACT: Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.
    Cell Reports 08/2013; · 7.21 Impact Factor
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    ABSTRACT: We demonstrate that JNK responds to substrate stiffness and regulates AJ formation in epithelial cells in 2D cultures and in 3D tissues in vitro and in vivo. Rigid substrates led to JNK activation and AJ disassembly, while soft matrices suppressed JNK activity leading to AJ formation. Expression of constitutively active JNK (MKK7-JNK1) induced AJ dissolution even on soft substrates, while JNK knockdown (shJNK) induced AJ formation even on hard substrates. In human epidermis, basal cells expressed phosphorylated (p)-JNK but lacked AJ, while suprabasal keratinocytes contained strong AJ but lacked p-JNK. AJ formation was significantly impaired even in the upper suprabasal layers of bioengineered epidermis when prepared with stiffer scaffold or MKK7-JNK1 expressing keratinocytes. In contrast, shJNK1 or shJNK2 epidermis exhibited strong AJ even in the basal layer. The results with bioengineered epidermis were in full agreement with the epidermis of jnk1(-/-) or jnk2(-/-) mice. In conclusion, we propose that JNK mediates the effects of substrate stiffness on AJ formation in 2D and 3D context in vitro as well as in vivo.
    Journal of Cell Science 04/2013; · 5.33 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS:: Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH) deficient mice are hypophagic, lean and do not develop hepatosteatosis when fed on high fat diet. Herein, we sought to investigate the role of melanin-concentrating hormone (MCH), an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area (LHA), on hepatic and adipocyte metabolism. METHODS:: Chronic central administration of MCH and adenoviral vectors increasing MCH signalling were performed in rats and mice. Vagal dennervation was done to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time PCR and western blot. RESULTS:: We demonstrate that the activation of MCH receptors (MCH-R) promotes nonalcoholic fatty liver disease (NAFLD) through the parasympathetic nervous system (PSNS), whereas it increases fat deposition in WAT via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, being c-Jun N-terminal kinase (JNK1) an essential player, while in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH-R or infusion of MCH specifically in the LHA modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus (ARC) affected adipocyte metabolism. CONCLUSIONS:: Our findings reveal that central MCH directly controls hepatic and adipocyte metabolism through different pathways.
    Gastroenterology 03/2013; 144(3):636-649. · 12.82 Impact Factor
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    ABSTRACT: The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor (PPAR)α and PPARγ in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in beta-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on beta-oxidation. Thus, the function of ACSL1 varies in different tissues. We therefore investigated the signals and signal transduction pathways resulting in ACSL1 induction in macrophages, as well as the consequences of ACSL1 deficiency for phospholipid turnover in LPS-activated macrophages. LPS, Gram-negative bacteria, IFN-γ and TNFαall induce ACSL1 expression in macrophages, whereas PPAR agonists do not. LPS-induced ACSL1 expression is dependent on toll-like receptor 4 (TLR4) and its adapter protein TRIF (toll-like receptor adaptor molecule 1), but does not require the MyD88 (myeloid differentiation primary response gene 88) arm of TLR4 signaling, nor does it require STAT1 (signal transducer and activator of transcription 1) for maximal induction. Furthermore, ACSL1 deletion attenuates phospholipid turnover in LPS-stimulated macrophages. Thus, the regulation and biological function of ACSL1 in macrophages differs markedly from that in insulin target tissues. These results suggest that ACSL1 may have an important role in the innate immune response. Further, these findings illustrate an interesting paradigm in which the same enzyme, ACSL1, confers distinct biological effects in different cell types, and these disparate functions are paralleled by differences in the pathways that regulate its expression.
    Journal of Biological Chemistry 02/2013; · 4.60 Impact Factor
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    ABSTRACT: This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between β1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2013; · 3.87 Impact Factor
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    ABSTRACT: The cJun NH2-terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated in this process. To test the role of JNK, we established mice with selective JNK deficiency in macrophages. We report that feeding a high-fat diet to control and JNK-deficient mice caused similar obesity, but only mice with JNK-deficient macrophages remained insulin-sensitive. The protection of mice with macrophage-specific JNK deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotyping demonstrated that JNK was required for pro-inflammatory macrophage polarization. These studies demonstrate that JNK in macrophages is required for the establishment of obesity-induced insulin resistance and inflammation.
    Science 01/2013; 339(6116):218-222. · 31.48 Impact Factor
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    ABSTRACT: Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.
    The Journal of clinical investigation 12/2012; · 15.39 Impact Factor
  • Roger J Davis
    Science 09/2012; 337(6099):1178-9. · 31.48 Impact Factor
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    ABSTRACT: Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G 2/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, thereby preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.
    Cell cycle (Georgetown, Tex.) 08/2012; 11(19):3627-37. · 5.24 Impact Factor
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    ABSTRACT: We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.
    Cancer Discovery 07/2012; 2(10):906-921. · 15.93 Impact Factor

Publication Stats

15k Citations
1,902.43 Total Impact Points


  • 1992–2014
    • University of Massachusetts Medical School
      • • Program in Molecular Medicine
      • • Department of Biochemistry and Molecular Pharmacology
      Worcester, Massachusetts, United States
  • 1994–2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2009–2011
    • Massachusetts Institute of Technology
      • Department of Biological Engineering
      Cambridge, Massachusetts, United States
  • 2001–2011
    • University of Vermont
      • • Department of Surgery
      • • Department of Medicine
      Burlington, VT, United States
  • 2010
    • Yeshiva University
      New York City, New York, United States
    • National Center for Biotechnology (CNB)
      Madrid, Madrid, Spain
  • 2004–2009
    • University of Dundee
      • • College of Life Sciences
      • • MRC Protein Phosphorylation Unit
      Dundee, SCT, United Kingdom
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, ENG, United Kingdom
  • 2000–2009
    • Yale University
      • • Department of Immunobiology
      • • Section of Pulmonary and Critical Care Medicine
      New Haven, Connecticut, United States
  • 2008
    • University of Massachusetts Amherst
      Amherst Center, Massachusetts, United States
  • 2002–2008
    • University of Ottawa
      Ottawa, Ontario, Canada
    • Stony Brook University
      • Department of Molecular Genetics and Microbiology
      Stony Brook, New York, United States
    • University of Washington Seattle
      • Department of Immunology
      Seattle, WA, United States
  • 2007
    • Albert Einstein College of Medicine
      • Department of Molecular Pharmacology
      New York City, NY, United States
  • 2003–2007
    • King's College London
      • Cardiovascular Division
      London, ENG, United Kingdom
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
    • Roche
      Bâle, Basel-City, Switzerland
    • NCI-Frederick
      Maryland, United States
  • 2006
    • University of California, Davis
      Davis, California, United States
  • 2005
    • Columbia University
      • Department of Medicine
      New York City, NY, United States