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Results: 1 to 10 of 17

Publication Record


Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9.
Rhoads JP, Lukens JR, Wilhelm AJ, Moore JL, Mendez-Fernandez Y, Kanneganti TD, Major AS
(2017) J Immunol 198: 2105-2114
MeSH Terms: Animals, Antibodies, Antigen-Antibody Complex, CARD Signaling Adaptor Proteins, Cells, Cultured, Cytokines, Dendritic Cells, Inflammasomes, Inflammation Mediators, Lipoproteins, LDL, Macrophages, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Receptor Cross-Talk, Receptors, IgG, Signal Transduction, Th17 Cells, Toll-Like Receptors
Show Abstract · Added March 30, 2020
Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Interestingly, much of the oxLDL in circulation is complexed to Abs, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease, such as atherosclerosis, type-2 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL ICs often correlate with disease severity, and studies demonstrated that oxLDL ICs elicit potent inflammatory responses in macrophages. In this article, we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL ICs for 24 h secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, whereas there was no difference in levels of TNF-α or IL-6. Treatment of BMDCs with oxLDL ICs increased expression of inflammasome-related genes , , and , and pretreatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL ICs. This inflammasome priming was due to oxLDL IC signaling via multiple receptors, because inhibition of CD36, TLR4, and FcγR significantly decreased IL-1β secretion in response to oxLDL ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-κB translocation. Finally, oxLDL IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction.
Shi C, Washington MK, Chaturvedi R, Drosos Y, Revetta FL, Weaver CJ, Buzhardt E, Yull FE, Blackwell TS, Sosa-Pineda B, Whitehead RH, Beauchamp RD, Wilson KT, Means AL
(2014) Lab Invest 94: 409-21
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Cell Line, Disease Models, Animal, Disease Progression, Fibrosis, Macrophages, Metaplasia, Mice, Pancreas, Pancreatic Neoplasms, Pancreatic Stellate Cells, Receptor Cross-Talk
Show Abstract · Added March 5, 2014
Pancreatic cancer occurs in the setting of a profound fibrotic microenvironment that often dwarfs the actual tumor. Although pancreatic fibrosis has been well studied in chronic pancreatitis, its development in pancreatic cancer is much less well understood. This article describes the dynamic remodeling that occurs from pancreatic precursors (pancreatic intraepithelial neoplasias (PanINs)) to pancreatic ductal adenocarcinoma, highlighting similarities and differences between benign and malignant disease. Although collagen matrix is a commonality throughout this process, early stage PanINs are virtually free of periostin while late stage PanIN and pancreatic cancer are surrounded by an increasing abundance of this extracellular matrix protein. Myofibroblasts also become increasingly abundant during progression from PanIN to cancer. From the earliest stages of fibrogenesis, macrophages are associated with this ongoing process. In vitro co-culture indicates there is cross-regulation between macrophages and pancreatic stellate cells (PaSCs), precursors to at least some of the fibrotic cell populations. When quiescent PaSCs were co-cultured with macrophage cell lines, the stellate cells became activated and the macrophages increased cytokine production. In summary, fibrosis in pancreatic cancer involves a complex interplay of cells and matrices that regulate not only the tumor epithelium but the composition of the microenvironment itself.
1 Communities
6 Members
0 Resources
13 MeSH Terms
Glomerular cell cross-talk influences composition and assembly of extracellular matrix.
Byron A, Randles MJ, Humphries JD, Mironov A, Hamidi H, Harris S, Mathieson PW, Saleem MA, Satchell SC, Zent R, Humphries MJ, Lennon R
(2014) J Am Soc Nephrol 25: 953-66
MeSH Terms: Cells, Cultured, Coculture Techniques, Culture Media, Conditioned, Extracellular Matrix, Extracellular Matrix Proteins, Humans, Kidney Glomerulus, Phenotype, Podocytes, Protein Interaction Maps, Receptor Cross-Talk
Show Abstract · Added February 25, 2014
The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore, functionally linked to glomerular filtration. Although the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM are not well understood. To characterize specific cellular contributions to the GBM, we used mass spectrometry-based proteomics to analyze ECM isolated from podocytes and glomerular endothelial cells in vitro. These analyses identified cell type-specific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared with monoculture ECMs, and electron microscopy revealed basement membrane-like ECM deposition between cocultured cells, suggesting the involvement of cell-cell cross-talk in the production of glomerular ECM. Notably, compared with monoculture ECM proteomes, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings show the complexity of the glomerular ECM and suggest that both ECM composition and organization are context-dependent.
Copyright © 2014 by the American Society of Nephrology.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor.
Guckes KR, Kostakioti M, Breland EJ, Gu AP, Shaffer CL, Martinez CR, Hultgren SJ, Hadjifrangiskou M
(2013) Proc Natl Acad Sci U S A 110: 16592-7
MeSH Terms: Bacterial Proteins, DNA Primers, DNA Transposable Elements, Electrophoretic Mobility Shift Assay, Escherichia coli, Escherichia coli Proteins, Gene Expression Regulation, Bacterial, Immunoblotting, Mutagenesis, Quorum Sensing, Real-Time Polymerase Chain Reaction, Receptor Cross-Talk, Signal Transduction
Show Abstract · Added August 6, 2014
Bacterial two-component systems (TCSs) mediate specific responses to distinct conditions and/or stresses. TCS interactions are highly specific between cognate partners to avoid unintended cross-talk. Although cross-talk between a sensor kinase and a noncognate response regulator has been previously demonstrated, the majority of reported interactions have not been robust. Here, we report that in the case of the quorum-sensing Escherichia coli (Qse)BC TCS, absence of the cognate sensor QseC leads to robust, constitutive activation of the QseB response regulator by the noncognate polymyxin resistance (Pmr) sensor kinase PmrB. Remarkably, the noncognate PmrB exhibits a kinetic preference for QseB that is similar to QseC. However, although PmrB readily phosphorylates QseB in vitro, it is significantly less efficient at dephosphorylating QseB, compared with QseC, thereby explaining the increased levels of active QseB in the qseC mutant. In addition to PmrB activating QseB on the protein level, we found that the PmrA response regulator contributes to qseB transcription in the absence of QseC and PmrA specifically binds the qseBC promoter, indicative of a direct regulation of qseBC gene transcription by PmrAB under physiological conditions. Addition of ferric iron in the growth medium of wild-type uropathogenic E. coli induced the expression of qseBC in a PmrB-dependent manner. Taken together, our findings suggest that (i) robust cross-talk between noncognate partners is possible and (ii) this interaction can be manipulated for the development of antivirulence strategies aimed at targeting uropathogenic Escherichia coli and potentially other QseBC-PmrAB-bearing pathogens.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling.
McGuire VA, Gray A, Monk CE, Santos SG, Lee K, Aubareda A, Crowe J, Ronkina N, Schwermann J, Batty IH, Leslie NR, Dean JL, O'Keefe SJ, Boothby M, Gaestel M, Arthur JS
(2013) Mol Cell Biol 33: 4152-65
MeSH Terms: Animals, Cell Line, Enzyme Activation, Heat-Shock Proteins, Imidazoles, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinase 14, Neoplasm Proteins, Phosphatidylinositol Phosphates, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyridazines, Pyridines, Pyrimidines, Receptor Cross-Talk, Signal Transduction, Toll-Like Receptors
Show Abstract · Added March 7, 2014
The stimulation of Toll-like receptors (TLRs) on macrophages by pathogen-associated molecular patterns (PAMPs) results in the activation of intracellular signaling pathways that are required for initiating a host immune response. Both phosphatidylinositol 3-kinase (PI3K)-Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways are activated rapidly in response to TLR activation and are required to coordinate effective host responses to pathogen invasion. In this study, we analyzed the role of the p38-dependent kinases MK2/3 in the activation of Akt and show that lipopolysaccharide (LPS)-induced phosphorylation of Akt on Thr308 and Ser473 requires p38α and MK2/3. In cells treated with p38 inhibitors or an MK2/3 inhibitor, phosphorylation of Akt on Ser473 and Thr308 is reduced and Akt activity is inhibited. Furthermore, BMDMs deficient in MK2/3 display greatly reduced phosphorylation of Ser473 and Thr308 following TLR stimulation. However, MK2/3 do not directly phosphorylate Akt in macrophages but act upstream of PDK1 and mTORC2 to regulate Akt phosphorylation. Akt is recruited to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the membrane, where it is activated by PDK1 and mTORC2. Analysis of lipid levels in MK2/3-deficient bone marrow-derived macrophages (BMDMs) revealed a role for MK2/3 in regulating Akt activity by affecting availability of PIP3 at the membrane. These data describe a novel role for p38α-MK2/3 in regulating TLR-induced Akt activation in macrophages.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Modelling cell polarization driven by synthetic spatially graded Rac activation.
Holmes WR, Lin B, Levchenko A, Edelstein-Keshet L
(2012) PLoS Comput Biol 8: e1002366
MeSH Terms: Cell Membrane, Cell Polarity, Cell Shape, Computational Biology, Computer Simulation, Cytosol, Enzyme Activation, Feedback, Physiological, HeLa Cells, Humans, Models, Biological, Phosphatidylinositols, Receptor Cross-Talk, cdc42 GTP-Binding Protein, rac GTP-Binding Proteins, rho GTP-Binding Proteins
Show Abstract · Added February 26, 2016
The small GTPase Rac is known to be an important regulator of cell polarization, cytoskeletal reorganization, and motility of mammalian cells. In recent microfluidic experiments, HeLa cells endowed with appropriate constructs were subjected to gradients of the small molecule rapamycin leading to synthetic membrane recruitment of a Rac activator and direct graded activation of membrane-associated Rac. Rac activation could thus be triggered independent of upstream signaling mechanisms otherwise responsible for transducing activating gradient signals. The response of the cells to such stimulation depended on exceeding a threshold of activated Rac. Here we develop a minimal reaction-diffusion model for the GTPase network alone and for GTPase-phosphoinositide crosstalk that is consistent with experimental observations for the polarization of the cells. The modeling suggests that mutual inhibition is a more likely mode of cell polarization than positive feedback of Rac onto its own activation. We use a new analytical tool, Local Perturbation Analysis, to approximate the partial differential equations by ordinary differential equations for local and global variables. This method helps to analyze the parameter space and behaviour of the proposed models. The models and experiments suggest that (1) spatially uniform stimulation serves to sensitize a cell to applied gradients. (2) Feedback between phosphoinositides and Rho GTPases sensitizes a cell. (3) Cell lengthening/flattening accompanying polarization can increase the sensitivity of a cell and stabilize an otherwise unstable polarization.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Does lapatinib work against HER2-negative breast cancers?
Mayer IA, Arteaga CL
(2010) Clin Cancer Res 16: 1355-7
MeSH Terms: Animals, Antineoplastic Agents, Breast Neoplasms, Clinical Trials as Topic, Drug Resistance, Neoplasm, Female, Humans, Lapatinib, Quinazolines, Receptor Cross-Talk, Receptor, ErbB-2, Receptors, Estrogen
Show Abstract · Added March 5, 2014
Aberrant growth factor receptor signaling can augment or suppress estrogen receptor (ER) function in hormone-dependent breast cancer cells and lead to escape from anti-estrogen therapy. Interruption of HER2/ER cross-talk with lapatinib can restore sensitivity to anti-estrogens and thus, should be investigated in combination with endocrine therapy in patients with ER+/HER2-negative breast cancers.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis.
Ricono JM, Huang M, Barnes LA, Lau SK, Weis SM, Schlaepfer DD, Hanks SK, Cheresh DA
(2009) Cancer Res 69: 1383-91
MeSH Terms: Animals, Carcinoma, Cell Movement, Chick Embryo, DNA Primers, Epidermal Growth Factor, ErbB Receptors, Gene Knockdown Techniques, Humans, Inverted Repeat Sequences, Lung, Lung Neoplasms, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Pancreatic Neoplasms, Polymerase Chain Reaction, RNA, Neoplasm, Receptor Cross-Talk, Receptors, Vitronectin, Tumor Cells, Cultured
Show Abstract · Added January 20, 2015
Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin alpha(v)beta(5). Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)-induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and alpha(v)beta(5) activation. This pathway induces alpha(v)beta(5)-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton.
Wang SE, Xiang B, Zent R, Quaranta V, Pozzi A, Arteaga CL
(2009) Cancer Res 69: 475-82
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Breast Neoplasms, Cell Line, Tumor, Cell Membrane, Cytoskeleton, Enzyme Activation, ErbB Receptors, Focal Adhesion Kinase 1, Humans, Integrins, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor Cross-Talk, Receptor, ErbB-2, Transforming Growth Factor beta, Trastuzumab, src-Family Kinases
Show Abstract · Added February 24, 2014
It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2-mediated mammary tumorigenesis. Here we show that transforming growth factor beta (TGF-beta) induced focal adhesion kinase (FAK)-dependent clustering of HER2 and integrins alpha(6), beta(1), and beta(4) in HER2-overexpressing mammary epithelial cells without altering the total and surface levels of HER2 receptors. This effect was mediated by ligand-induced epidermal growth factor receptor (EGFR) activation and the subsequent phosphorylation of Src and FAK. We have previously reported that TGF-beta up-regulates EGFR ligand shedding through a mechanism involving the phosphorylation of tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin alpha(6) by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-beta-induced receptor clustering and signaling to phosphatidylinositol 3-kinase-Akt. Finally, inhibition of Src-FAK reversed TGF-beta-induced resistance to the therapeutic HER2 inhibitor trastuzumab in HER2-overexpressing breast cancer cells. Taken together, these data suggest that, by activating Src-FAK, TGF-beta integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression.
3 Communities
3 Members
0 Resources
18 MeSH Terms
G-protein-coupled receptors: evolving views on physiological signalling: symposium on G-protein-coupled receptors: evolving concepts and new techniques.
Holinstat M, Oldham WM, Hamm HE
(2006) EMBO Rep 7: 866-9
MeSH Terms: Dimerization, GTP-Binding Proteins, Humans, Models, Biological, Receptor Cross-Talk, Receptors, G-Protein-Coupled, Signal Transduction, Structure-Activity Relationship
Added January 20, 2015
0 Communities
1 Members
0 Resources
8 MeSH Terms