What is the significance of canonical pathways

Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers...

Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines...

Abstract The majority of heritable pulmonary arterial hypertension (HPAH) cases are associated with mutations in bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation carries about a 20% lifetime risk of PAH development, but penetrance is approximately three times higher in females. Previous studies have shown a correlation between estrogen metabolism and penetrance, with increased levels of the estrogen metabolite 16α-hydroxyestrone (16αOHE) and reduced levels of the metabolite 2-methoxyestrogen (2ME) associated with increased risk of disease...

Toll-like receptors (TLRs) bind to components of microbes, activate cellular signal transduction pathways and stimulate innate immune responses. Previously, we have shown in chicken monocytes that the combination of CpG, the ligand for TLR21 (the chicken equivalent of TLR9), and poly I:C, the ligand for TLR3, results in a synergistic immune response. In order to further characterize this synergy, kinome analysis was performed on chicken monocytes stimulated with either unmethylated CpG oligodeoxynucleotides (CpG) and polyinosinic-polycytidylic acid (poly I:C) individually or in combination for either 1h or 4h...

BACKGROUND: The carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP. However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle. Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved...

Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression-based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation...

Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined...

Although the activation of the A(1)-subtype of the adenosine receptors (A(1)AR) is arrhythmogenic in the developing heart, little is known about the underlying downstream mechanisms. The aim of this study was to determine to what extent the transient receptor potential canonical (TRPC) channel 3, functioning as receptor-operated channel (ROC), contributes to the A(1)AR-induced conduction disturbances. Using embryonic atrial and ventricular myocytes obtained from 4-day-old chick embryos, we found that the specific activation of A(1)AR by CCPA induced sarcolemmal Ca(2+) entry...

The unlimited proliferation potential of cancer cells requires the maintenance of their telomeres. This is frequently accomplished by reactivation of telomerase. However, in a significant fraction of tumors an alternative lengthening of telomeres (ALT) mechanism is active. The molecular mechanism of the ALT pathway remains elusive. In particular, the role of characteristic complexes of promyelocytic leukemia nuclear bodies (PML-NBs) with telomeres, the ALT-associated PML-NBs (APBs), is currently under investigation...

INTRODUCTION: Peyronie's disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytren's disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated with DD. Seven of these loci mapped within or near genes of the canonical WNT pathway and each locus yielded relatively large odds ratios (ORs) for DD disease status. AIM: Given the clinical overlap between PD and DD, we examined whether the nine DD susceptibility loci are also involved in PD...

A well-defined granular layer 4 is a defining cytoarchitectonic feature associated with sensory areas of mammalian cerebral cortex, and one with hodological significance: the local axons ascending from cells in thalamorecipient layer 4 and connecting to layer 2/3 pyramidal neurons form a major feedforward excitatory interlaminar projection. Conversely, agranular cortical areas, lacking a distinct layer 4, pose a hodological conundrum: without a laminar basis for the canonical layer 4-->2/3 pathway, what is the basic circuit organization? This review highlights current challenges and prospects for local-circuit electroanatomy and electrophysiology in agranular cortex, focusing on the mouse...

Low cellular oxygenation (hypoxia) represents a significant threat to the viability of affected tissues. Multicellular organisms have evolved a highly conserved signalling pathway that directs many of the changes in gene expression that underpin physiological oxygen homoeostasis. Oxygen-sensing enzymes in this pathway control the activity of the HIF (hypoxia-inducible factor) transcription factor by the direct incorporation of molecular oxygen into the post-translational hydroxylation of specific residues. This represents the canonical hypoxia signalling pathway which regulates a plethora of genes involved in adaptation to hypoxia...

In the Drosophila retina, photoreceptor differentiation is preceded by significant cell shape rearrangements within and immediately behind the morphogenetic furrow. Groups of cells become clustered into arcs and rosettes in the plane of the epithelium, from which the neurons subsequently emerge. These cell clusters also have differential adhesive properties: adherens junction components are upregulated relative to surrounding cells. Little is known about how these morphological changes are orchestrated and what their relevance is for subsequent neuronal differentiation...