Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 147

Publication Record

Connections

Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification.
Perry NA, Kaoud TS, Ortega OO, Kaya AI, Marcus DJ, Pleinis JM, Berndt S, Chen Q, Zhan X, Dalby KN, Lopez CF, Iverson TM, Gurevich VV
(2019) Proc Natl Acad Sci U S A 116: 810-815
MeSH Terms: MAP Kinase Kinase 4, MAP Kinase Kinase 7, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 10, Models, Biological, Phosphorylation, Software, beta-Arrestin 2
Show Abstract · Added April 1, 2019
Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a "conveyor belt" mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.
0 Communities
1 Members
0 Resources
MeSH Terms
Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling.
Stark RJ, Koch SR, Choi H, Mace EH, Dikalov SI, Sherwood ER, Lamb FS
(2018) FASEB J 32: 945-956
MeSH Terms: Capillary Permeability, Cells, Cultured, Chronic Disease, Endothelial Cells, Gene Expression Regulation, Enzymologic, Humans, Imidazoles, Interleukin-6, Lipopolysaccharides, MAP Kinase Signaling System, Nitric Oxide, Nitric Oxide Synthase Type III, Pyridines, Toll-Like Receptor 4, Vasculitis, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added October 27, 2017
Endothelial dysfunction, characterized by changes in eNOS, is a common finding in chronic inflammatory vascular diseases. These states are associated with increased infectious complications. We hypothesized that alterations in eNOS would enhance the response to LPS-mediated TLR4 inflammation. Human microvascular endothelial cells were treated with sepiapterin or N-nitro-L-arginine methylester (L-NAME) to alter endogenous NO production, and small interfering RNA to knockdown eNOS. Alterations of endogenous NO by sepiapterin, and L-NAME provided no significant changes to LPS inflammation. In contrast, eNOS knockdown greatly enhanced endothelial IL-6 production and permeability in response to LPS. Knockdown of eNOS enhanced LPS-induced p38. Inhibition of p38 with SB203580 prevented IL-6 production, without altering permeability. Knockdown of p38 impaired NF-κB activation. Physical interaction between p38 and eNOS was demonstrated by immunoprecipitation, suggesting a novel, NO-independent mechanism for eNOS regulation of TLR4. In correlation, biopsy samples in patients with systemic lupus erythematous showed reduced eNOS expression with associated elevations in TLR4 and p38, suggesting an in vivo link. Thus, reduced expression of eNOS, as seen in chronic inflammatory disease, was associated with enhanced TLR4 signaling through p38. This may enhance the response to infection in patients with chronic inflammatory conditions.-Stark, R. J., Koch, S. R., Choi, H., Mace, E. H., Dikalov, S. I., Sherwood, E. R., Lamb, F. S. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling.
0 Communities
3 Members
0 Resources
16 MeSH Terms
Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
Dushyanthen S, Teo ZL, Caramia F, Savas P, Mintoff CP, Virassamy B, Henderson MA, Luen SJ, Mansour M, Kershaw MH, Trapani JA, Neeson PJ, Salgado R, McArthur GA, Balko JM, Beavis PA, Darcy PK, Loi S
(2017) Nat Commun 8: 606
MeSH Terms: 4-1BB Ligand, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mammary Neoplasms, Animal, Mice, OX40 Ligand, Protein Kinase Inhibitors, Pyridones, Pyrimidinones, T-Lymphocyte Subsets, T-Lymphocytes, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.
0 Communities
1 Members
0 Resources
21 MeSH Terms
The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1.
Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR
(2017) Cell Death Differ 24: 855-865
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Communication, Cell Count, Cell Differentiation, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Regulation, HT29 Cells, Humans, Ileum, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Paneth Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-3, Receptors, G-Protein-Coupled, Stem Cell Niche, Stem Cells
Show Abstract · Added October 16, 2018
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche. Intestinal epithelial ErbB3 knockout caused precocious appearance of PCs as early as postnatal day 7, and substantially increased the number of mature PCs in adult mouse ileum. ErbB3 loss had no effect on other secretory lineages, but increased expression of the ISC marker Lgr5. ErbB3-null intestines had elevated levels of the Atoh1 transcription factor, which is required for secretory fate determination, while Atoh1 cells had reduced ErbB3, suggesting reciprocal negative regulation. ErbB3-null intestinal progenitor cells showed reduced activation of the PI3K-Akt and ERK MAPK pathways. Inhibiting these pathways in HT29 cells increased levels of ATOH1 and the PC marker LYZ. Conversely, ErbB3 activation suppressed LYZ and ATOH1 in a PI3K-dependent manner. Expansion of the PC compartment in ErbB3-null intestines was accompanied with elevated ER stress and inflammation markers, raising the possibility that negative regulation of PCs by ErbB3 is necessary to maintain homeostasis. Taken together, our data suggest that ErbB3 restricts PC numbers through PI3K-mediated suppression of Atoh1 levels leading to inhibition of PC differentiation, with important implications for regulation of the ISC niche.
0 Communities
1 Members
0 Resources
MeSH Terms
Impaired coordination between signaling pathways is revealed in human colorectal cancer using single-cell mass cytometry of archival tissue blocks.
Simmons AJ, Scurrah CR, McKinley ET, Herring CA, Irish JM, Washington MK, Coffey RJ, Lau KS
(2016) Sci Signal 9: rs11
MeSH Terms: Animals, Colorectal Neoplasms, Female, Humans, Image Cytometry, MAP Kinase Signaling System, Male, Mass Spectrometry, Mice, Neoplasm Proteins, Paraffin Embedding
Show Abstract · Added October 19, 2016
Cellular heterogeneity poses a substantial challenge to understanding tissue-level phenotypes and confounds conventional bulk analyses. To analyze signaling at the single-cell level in human tissues, we applied mass cytometry using cytometry time of flight to formalin-fixed, paraffin-embedded (FFPE) normal and diseased intestinal specimens. This technique, called FFPE-DISSECT (disaggregation for intracellular signaling in single epithelial cells from tissue), is a single-cell approach to characterizing signaling states in embedded tissue samples. We applied FFPE-DISSECT coupled to mass cytometry and found differential signaling by tumor necrosis factor-α in intestinal enterocytes, goblet cells, and enteroendocrine cells, implicating the downstream RAS-RAF-MEK pathway in determining goblet cell identity. Application of this technique and computational analyses to human colon specimens confirmed the reduced differentiation in colorectal cancer (CRC) compared to normal colon and revealed increased intratissue and intertissue heterogeneity in CRC with quantitative changes in the regulation of signaling pathways. Specifically, coregulation of the kinases p38 and ERK, the translation regulator 4EBP1, and the transcription factor CREB in proliferating normal colon cells was lost in CRC. Our data suggest that this single-cell approach, applied in conjunction with genomic annotation, enables the rapid and detailed characterization of cellular heterogeneity from clinical repositories of embedded human tissues. This technique can be used to derive cellular landscapes from archived patient samples (beyond CRC) and as a high-resolution tool for disease characterization and subtyping.
Copyright © 2016, American Association for the Advancement of Science.
2 Communities
4 Members
0 Resources
11 MeSH Terms
The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.
Ma Y, Wang L, Neitzel LR, Loganathan SN, Tang N, Qin L, Crispi EE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J
(2017) Clin Cancer Res 23: 2027-2037
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Nuclear Proteins, Real-Time Polymerase Chain Reaction, Transcription Factors, Xenograft Model Antitumor Assays
Show Abstract · Added November 19, 2016
The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer. Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches. BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulation and A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts. Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer. .
©2016 American Association for Cancer Research.
0 Communities
4 Members
0 Resources
17 MeSH Terms
Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery.
Sengmany K, Singh J, Stewart GD, Conn PJ, Christopoulos A, Gregory KJ
(2017) Neuropharmacology 115: 60-72
MeSH Terms: Allosteric Regulation, Animals, Calcium Signaling, Dose-Response Relationship, Drug, Drug Discovery, Drug Evaluation, Preclinical, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Female, HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Receptor, Metabotropic Glutamate 5
Show Abstract · Added April 6, 2017
Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as 'biased agonism' and 'biased modulation'. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu) is a promising target. Current mGlu allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa) responses to orthosteric agonists alone. We assessed eight mGlu allosteric modulators previously classified as mGlu PAMs or PAM-agonists representing four distinct chemotypes across multiple measures of receptor activity, to explore their potential for engendering biased agonism and/or modulation. Relative to the reference orthosteric agonist, DHPG, the eight allosteric ligands exhibited distinct biased agonism fingerprints for iCa mobilization, IP accumulation and ERK1/2 phosphorylation in HEK293A cells stably expressing mGlu and in cortical neuron cultures. VU0424465, DPFE and VU0409551 displayed the most disparate biased signaling fingerprints in both HEK293A cells and cortical neurons that may account for the marked differences observed previously for these ligands in vivo. Select mGlu allosteric ligands also showed 'probe dependence' with respect to their cooperativity with different orthosteric agonists, as well as biased modulation for the magnitude of positive cooperativity observed. Unappreciated biased agonism and modulation may contribute to unanticipated effects (both therapeutic and adverse) when translating from recombinant systems to preclinical models. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Laminin-111 peptide C16 regulates invadopodia activity of malignant cells through β1 integrin, Src and ERK 1/2.
Siqueira AS, Pinto MP, Cruz MC, Smuczek B, Cruz KS, Barbuto JA, Hoshino D, Weaver AM, Freitas VM, Jaeger RG
(2016) Oncotarget 7: 47904-47917
MeSH Terms: Carcinoma, Squamous Cell, Cell Line, Tumor, Fibrosarcoma, Head and Neck Neoplasms, Humans, Integrin beta1, Laminin, MAP Kinase Signaling System, Mouth Neoplasms, Peptide Fragments, Podosomes, Squamous Cell Carcinoma of Head and Neck, Transfection, src-Family Kinases
Show Abstract · Added April 26, 2017
Laminin peptides influence tumor behavior. In this study, we addressed whether laminin peptide C16 (KAFDITYVRLKF, γ1 chain) would increase invadopodia activity of cells from squamous cell carcinoma (CAL27) and fibrosarcoma (HT1080). We found that C16 stimulates invadopodia activity over time in both cell lines. Rhodamine-conjugated C16 decorates the edge of cells, suggesting a possible binding to membrane receptors. Flow cytometry showed that C16 increases activated β1 integrin, and β1 integrin miRNA-mediated depletion diminishes C16-induced invadopodia activity in both cell lines. C16 stimulates Src and ERK 1/2 phosphorylation, and ERK 1/2 inhibition decreases peptide-induced invadopodia activity. C16 also increases cortactin phosphorylation in both cells lines. Based on our findings, we propose that C16 regulates invadopodia activity over time of squamous carcinoma and fibrosarcoma cells, probably through β1 integrin, Src and ERK 1/2 signaling pathways.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer.
Puvirajesinghe TM, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S, Sebbagh M, Lopez M, Brech A, Finetti P, Charafe-Jauffret E, Chaffanet M, Castellano R, Restouin A, Marchetto S, Collette Y, Gonçalvès A, Macara I, Birnbaum D, Kodjabachian L, Johansen T, Borg JP
(2016) Nat Commun 7: 10318
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Blotting, Western, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Cell Line, Tumor, Cell Migration Assays, Cell Movement, Cell Polarity, Cell Proliferation, DNA Copy Number Variations, Embryo, Nonmammalian, Female, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Mass Spectrometry, Membrane Proteins, Mice, Microscopy, Electron, Middle Aged, Neoplasm Transplantation, Prognosis, Proportional Hazards Models, RNA, Messenger, Sequestosome-1 Protein, Wnt Signaling Pathway, Xenopus
Show Abstract · Added April 10, 2018
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1-JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2-p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy.
0 Communities
1 Members
0 Resources
MeSH Terms
MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer.
Edmonds MD, Boyd KL, Moyo T, Mitra R, Duszynski R, Arrate MP, Chen X, Zhao Z, Blackwell TS, Andl T, Eischen CM
(2016) J Clin Invest 126: 349-64
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Female, Humans, Lung Neoplasms, MAP Kinase Signaling System, Male, Mice, MicroRNAs, Mutation, NIH 3T3 Cells, Proto-Oncogene Proteins p21(ras), ras Proteins
Show Abstract · Added February 22, 2016
MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
1 Communities
1 Members
0 Resources
15 MeSH Terms