ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans.

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity.

VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain.

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion.

Transsynaptic Signaling of Ephs in Synaptic Development, Plasticity, and Disease.

Synapse formation between neurons is critical for proper circuit and brain function. Prior to activity-dependent refinement of connections between neurons, activity-independent cues regulate the contact and recognition of potential synaptic partners. Formation of a synapse results in molecular recognition events that initiate the process of synaptogenesis.

A novel Pyk2-derived peptide inhibits invadopodia-mediated breast cancer metastasis.

Dissemination of cancer cells from the primary tumor into distant body tissues and organs is the leading cause of death in cancer patients. While most clinical strategies aim to reduce or impede the growth of the primary tumor, no treatment to eradicate metastatic cancer exists at present. Metastasis is mediated by feet-like cytoskeletal structures called invadopodia which allow cells to penetrate through the basement membrane and intravasate into blood vessels during their spread to distant tissues and organs.

FAK-Mediated Signaling Controls Amyloid Beta Overload, Learning and Memory Deficits in a Mouse Model of Alzheimer's Disease.

The non-receptor focal adhesion kinase (FAK) is highly expressed in the central nervous system during development, where it regulates neurite outgrowth and axon guidance, but its role in the adult healthy and diseased brain, specifically in Alzheimer's disease (AD), is largely unknown. Using the 3xTg-AD mouse model, which carries three mutations associated with familial Alzheimer's disease (APP KM670/671NL Swedish, PSEN1 M146V, MAPT P301L) and develops age-related progressive neuropathology including amyloid plaques and Tau tangles, we describe here, for the first time, the in vivo role of FAK in AD pathology. Our data demonstrate that while site-specific knockdown in the hippocampi of 3xTg-AD mice has no effect on learning and memory, hippocampal overexpression of the protein leads to a significant decrease in learning and memory capabilities, which is accompanied by a significant increase in amyloid β (Aβ) load.

Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic.

Pyk2 Stabilizes Striatal Medium Spiny Neuron Structure and Striatal-Dependent Action.

In day-to-day life, we often choose between pursuing familiar behaviors that have been rewarded in the past or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for flexibly arbitrating between old and new behavioral strategies. The way in which DMS neurons host stable connections necessary for sustained flexibility is still being defined.

Pyk2 regulates cell-edge protrusion dynamics by interacting with Crk.

Focal adhesion kinase (FAK) is well established as a regulator of cell migration, but whether and how the closely related proline-rich tyrosine kinase 2 (Pyk2) regulates fibroblast motility is still under debate. Using mouse embryonic fibroblasts (MEFs) from Pyk2 mice, we show here, for the first time, that lack of Pyk2 significantly impairs both random and directed fibroblast motility. Pyk2 MEFs show reduced cell-edge protrusion dynamics, which is dependent on both the kinase and protein-protein binding activities of Pyk2.

Cell Adhesion Factors in the Orbitofrontal Cortex Control Cue-Induced Reinstatement of Cocaine Seeking and Amygdala-Dependent Goal Seeking.

Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats).

Gestational diabetes induces behavioral and brain gene transcription dysregulation in adult offspring.

The etiology of Autism Spectrum Disorders (ASD) includes a strong genetic component and a complicated environmental component. Recent evidence indicates that maternal diabetes, including gestational diabetes, is associated with an increased prevalence of ASD. While previous studies have looked into possible roles for maternal diabetes in neurodevelopment, there are few studies into how gestational diabetes, with no previous diabetic or metabolic phenotype, may affect neurodevelopment.

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer's Disease Mice.

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer's disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis.

Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation.

Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide and the third cause of cancer-related mortality. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis, and eventually HCC. HCV is the most common risk factor for HCC in western countries and leads to a more aggressive and invasive disease with poorer patient survival rates.

L-Norvaline, a new therapeutic agent against Alzheimer's disease.

Growing evidence highlights the role of arginase activity in the manifestation of Alzheimer's disease (AD). Upregulation of arginase was shown to contribute to neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD.

L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer's Disease.

The urea cycle is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (Aβ) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase β-1 (S6K1) pathways promotes inflammation and oxidative stress.

Insights into the Functional Roles of N-Terminal and C-Terminal Domains of Helicobacter pylori DprA.

DNA processing protein A (DprA) plays a crucial role in the process of natural transformation. This is accomplished through binding and subsequent protection of incoming foreign DNA during the process of internalization. DprA along with Single stranded DNA binding protein A (SsbA) acts as an accessory factor for RecA mediated DNA strand exchange.