Search results for "SIG"

Specific role of N-methyl-D-aspartate (NMDA) receptor in elastin-derived VGVAPG peptide-dependent calcium homeostasis in mouse cortical astrocytes in…

2019

AbstractUnder physiological and pathological conditions, elastin is degraded to produce elastin-derived peptides (EDPs). EDPs are detected in the healthy human brain, and its concentration significantly increases after ischemic stroke. Both elastin and EDPs contains replications of the soluble VGVAPG hexapeptide, which has a broad range of biological activities. Effects of VGVAPG action are mainly mediated by elastin-binding protein (EBP), which is alternatively spliced, enzymatically inactive form of the GLB1 gene. This study was conducted to elucidate the activation and role of the N-methyl-D-aspartate receptor (NMDAR) in elastin-derived VGVAPG peptide-dependent calcium homeostasis in mou…

Assessing Human Genetic Variations in Glucose Transporter SLC2A10 and Their Role in Altering Structural and Functional Properties

2018

Purpose: Demand is increasing for clinical genomic sequencing to provide diagnoses for patients presenting phenotypes indicative of genetic diseases, but for whom routine genetic testing failed to yield a diagnosis. DNA-based testing using high-throughput technologies often identifies variants with insufficient evidence to determine whether they are disease-causal or benign, leading to categorization as variants of uncertain significance (VUS). Methods: We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (SLC2A10). Similar to many disease-relevant membrane proteins, no experimentally derived…

Antibody-mediated blockade of JMJD6 interaction with collagen I exerts antifibrotic and antimetastatic activities

2017

JMJD6 is known to localize in the nucleus, exerting histone arginine demethylase and lysyl hydroxylase activities. A novel localization of JMJD6 in the extracellular matrix, resulting from its secretion as a soluble protein, was unveiled by a new anti-JMJD6 mAb called P4E11, which was developed to identify new targets in the stroma. Recombinant JMJD6 binds with collagen type I (Coll-I), and distinct JMJD6 peptides interfere with collagen fibrillogenesis, collagen-fibronectin interaction, and adhesion of human tumor cells to the collagen substrate. P4E11 and collagen binding to JMJD6 are mutually exclusive because the amino acid sequences of JMJD6 necessary for the interaction with Coll-I ar…

Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse

2017

Numerous studies have been carried out in the mouse model, investigating the role of the CB1 cannabinoid receptor. However, mouse CB1 (mCB1) receptor differs from human CB1 (hCB1) receptor in 13 amino acid residues. Two splice variants, hCB1a and hCB1b, diverging in their amino-termini, have been reported to be unique for hCB1 and, via different signaling properties, contribute to CB1 receptor physiology and pathophysiology. We hypothesized that splice variants also exist for the mCB1 receptor and have different signaling properties. On murine hippocampal cDNA, we identified two novel mCB1 receptor splice variants generated by splicing of introns with 117 bp and 186 bp in the N-terminal dom…

Notch and TLR signaling coordinate monocyte cell fate and inflammation

2020

AbstractConventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of …

Beyond protein-coding genes

2019

A long non-coding RNA called lnc-NR2F1 regulates several neuronal genes, including some involved in autism and intellectual disabilities.

The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes

2017

Fibronectin (FN), a major extracellular matrix component, enables integrin-mediated cell adhesion via binding of α5β1, αIIbβ3 and αv-class integrins to an RGD-motif. An additional linkage for α5 and αIIb is the synergy site located in close proximity to the RGD motif. We report that mice with a dysfunctional FN-synergy motif (Fn1syn/syn) suffer from surprisingly mild platelet adhesion and bleeding defects due to delayed thrombus formation after vessel injury. Additional loss of β3 integrins dramatically aggravates the bleedings and severely compromises smooth muscle cell coverage of the vasculature leading to embryonic lethality. Cell-based studies revealed that the synergy site is dispensa…

2016

AbstractHuman papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX. Following internalisation, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein. Electron microscopy and immunofluorescence experiments indicate that the CD63-syntenin-1 complex controls delivery of internalised viral particles to multivesicular endosomes. Ac…

2016

AbstractShort posterior ciliary arteries (sPCA) provide the major blood supply to the optic nerve head. Emerging evidence has linked structural and functional anomalies of sPCA to the pathogenesis of several ocular disorders that cause varying degrees of visual loss, particularly anterior ischaemic optic neuropathy and glaucoma. Although the functional relevance of this vascular bed is well-recognized, the proteome of sPCA remains uncharacterized. Since the porcine ocular system closely resembles that of the human’s and is increasingly employed in translational ophthalmic research, this study characterized the proteome of porcine sPCA employing the mass spectrometry-based proteomics strateg…

2016

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors. Besides a number of Treg-associated molecules such as Foxp3, CTLA-4 or GARP, known to play critical roles in Treg differentiation, activation and function, the involvement of additional regulatory elements is suggested. Herein, kinase activities seem to play an important role in Treg fine tuning. Nevertheless, our knowledge regarding the complex intracellular signaling pathways controlling phenotype and functio…