E-Selectin-Dependent Signaling Via the Mitogen-Activated Protein Kinase Pathway in Vascular Endothelial Cells
81
Citation
51
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract E-selectin, a cytokine-inducible adhesion molecule, supports rolling and stable arrest of leukocytes on activated vascular endothelium. Previous studies have suggested that this transmembrane protein can also transduce signals into the endothelial cell. We now demonstrate activation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured HUVEC in response to E-selectin-dependent leukocyte adhesion and Ab-mediated cross-linking of cell surface E-selectin. Adhesion of increasing numbers of HL60 cells to IL-1β-activated HUVEC stimulated robust increases in MAPK activity that were abrogated by an E-selectin blocking Ab. Cross-linking of cell surface E-selectin with Abs, as a mimic of multivalent ligand engagement, strongly stimulated MAPK/extracellular signal-related kinase (ERK) kinase (MEK)-dependent MAPK activation and concomitant up-regulation of mRNA for c-fos, an immediate early response gene, whereas Ab cross-linking of HLA class I molecules (present at comparable density) failed to do so. Coimmunoprecipitation documented Ras, Raf-1 and, phospho-MEK complex formation. Unactivated HUVEC transduced with a full-length adenoviral E-selectin construct also exhibited cross-link-induced MAPK activation, macromolecular complex formation, and c-fos up-regulation, whereas HUVEC transduced with a cytoplasmic domain deletion mutant failed to respond. These observations indicate that E-selectin can transduce an activating stimulus via the MAPK cascade into the endothelial cell during leukocyte adhesion.Keywords:
MAPK cascade
Intercellular adhesion molecule
Nectin
Cell Signaling
Cite
Citations (86)
E-selectin
VCAM-1
Cell–cell interaction
Proinflammatory cytokine
Intercellular adhesion molecule
Cite
Citations (14)
JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.
MAPK cascade
Cite
Citations (19)
The ERK/MAPK cascade is one the four distinctive MAPK cascades which transmit extracellular signals to intracellular targets. This cascade has an important role in the regulation of several fundamental processes such as proliferation, differentiation and cell response to diverse extrinsic stresses. Moreover, several studies have shown participation of this cascade in the pathogenesis of cancer. Recent investigations have unraveled interaction between microRNAs (miRNAs) and ERK/MAPK cascade. These transcripts reside in both upstream and downstream of this cascade, regulating or being regulated by ERK/MAPK proteins. In the current review, we summarize the role of miRNAs in the regulation of ERK/MAPK and their contribution in the pathogenesis of human disorders with particular focus on cancers.
MAPK cascade
Pathogenesis
Cite
Citations (60)
Abstract This unit provides protocols to assay cell‐cell adhesion and adhesive‐dependent cellular functions mediated by calcium‐independent adhesion molecules. These protocols have been developed for neural cell adhesion molecules of the Ig superfamily. However, most of the protocols allow a more general application to other categories of adhesion molecules and non‐neural cells.
Immunoglobulin superfamily
Nectin
Cell–cell interaction
Cell Signaling
Cite
Citations (2)
Abstract Mitogen‐activated protein kinase (MAPK) cascades are key signaling modules downstream of receptors/sensors that perceive either endogenously produced stimuli such as peptide ligands and damage‐associated molecular patterns (DAMPs) or exogenously originated stimuli such as pathogen/microbe‐associated molecular patterns (P/MAMPs), pathogen‐derived effectors, and environmental factors. In this review, we provide a historic view of plant MAPK research and summarize recent advances in the establishment of MAPK cascades as essential components in plant immunity, response to environmental stresses, and normal growth and development. Each tier of the MAPK cascades is encoded by a small gene family, and multiple members can function redundantly in an MAPK cascade. Yet, they carry out a diverse array of biological functions in plants. How the signaling specificity is achieved has become an interesting topic of MAPK research. Future investigations into the molecular mechanism(s) underlying the regulation of MAPK activation including the activation kinetics and magnitude in response to a stimulus, the spatiotemporal expression patterns of all the components in the signaling pathway, and functional characterization of novel MAPK substrates are central to our understanding of MAPK functions and signaling specificity in plants.
MAPK cascade
Cite
Citations (297)
Mitogen-activated protein kinase (MAPK) cascade system is one of the highly conserved signal systems in eukaryotic cells, which participates in the regulation of many biological processes. Under the stimulation of different signals (such as cytokines, neurotransmitters, and hormones), MAPK cascade activates downstream targets and controls a variety of cellular processes, including growth, immunity, inflammation, and stress response. In different cells, the effects of MAPK cascade on cells vary with the stimuli and the duration of stimulation. MAPK cascade induces Th differentiation and participates in T cell receptor signal pathway and B cell receptor signal pathway. MAPK cascades regulate various cellular activities related to the occurrence and development of cancer. A thorough and systematic understanding of the specific regulatory effects of MAPK cascade on various cellular processes will provide theoretical guidance for treating various diseases.
MAPK cascade
Cite
Citations (3)
Nectin
Tumor progression
Cite
Citations (3)
Signaling via the Raf / MEK / ERK (MAPK) module controls multiple cell functions including proliferation, differentiation and survival. How this single pathway can regulate such diverse cell fates is unknown. Recently, we examined system outputs of the MAPK pathway from different cellular compartments. We observed robust activation of the MAPK cascade from both the plasma membrane and the Golgi. When the MAPK module is localized to plasma membrane nanoclusters corresponding to those occupied by activated H-, N- and K-ras, ERKpp output is digital, with both low and high Raf kinase inputs processed to generate a maximal ERKpp output. In contrast, when the MAPK module is localized to the Golgi, ERKpp output is graded such that Raf kinase input corresponds to ERKpp output. These results clearly demonstrate that different cellular environments available to the MAPK module can fundamentally rewire system output, which in turn may allow this single cascade to direct different cell fate decisions.
MAPK cascade
Cell fate determination
Cite
Citations (9)