scholarly journals The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases

2021 ◽  
Vol 13 ◽  
Author(s):  
Benoit de Pins ◽  
Tiago Mendes ◽  
Albert Giralt ◽  
Jean-Antoine Girault
Keyword(s):  
Tyrosine Kinase ◽  
Nmda Receptors ◽  
Receptor Tyrosine Kinase ◽  
Late Onset ◽  
Ischemia Reperfusion ◽  
Experimental Models ◽  
Src Family Kinases ◽  
Therapeutic Interventions ◽  
Negative Consequences ◽  
Amyloid Toxicity

Pyk2 is a non-receptor tyrosine kinase highly enriched in forebrain neurons. Pyk2 is closely related to focal adhesion kinase (FAK), which plays an important role in sensing cell contacts with extracellular matrix and other extracellular signals controlling adhesion and survival. Pyk2 shares some of FAK’s characteristics including recruitment of Src-family kinases after autophosphorylation, scaffolding by interacting with multiple partners, and activation of downstream signaling pathways. Pyk2, however, has the unique property to respond to increases in intracellular free Ca2+, which triggers its autophosphorylation following stimulation of various receptors including glutamate NMDA receptors. Pyk2 is dephosphorylated by the striatal-enriched phosphatase (STEP) that is highly expressed in the same neuronal populations. Pyk2 localization in neurons is dynamic, and altered following stimulation, with post-synaptic and nuclear enrichment. As a signaling protein Pyk2 is involved in multiple pathways resulting in sometimes opposing functions depending on experimental models. Thus Pyk2 has a dual role on neurites and dendritic spines. With Src family kinases Pyk2 participates in postsynaptic regulations including of NMDA receptors and is necessary for specific types of synaptic plasticity and spatial memory tasks. The diverse functions of Pyk2 are also illustrated by its role in pathology. Pyk2 is activated following epileptic seizures or ischemia-reperfusion and may contribute to the consequences of these insults whereas Pyk2 deficit may contribute to the hippocampal phenotype of Huntington’s disease. Pyk2 gene, PTK2B, is associated with the risk for late-onset Alzheimer’s disease. Studies of underlying mechanisms indicate a complex contribution with involvement in amyloid toxicity and tauopathy, combined with possible functional deficits in neurons and contribution in microglia. A role of Pyk2 has also been proposed in stress-induced depression and cocaine addiction. Pyk2 is also important for the mobility of astrocytes and glioblastoma cells. The implication of Pyk2 in various pathological conditions supports its potential interest for therapeutic interventions. This is possible through molecules inhibiting its activity or increasing it through inhibition of STEP or other means, depending on a precise evaluation of the balance between positive and negative consequences of Pyk2 actions.

Identification of Two Src Recruitment Sites in the Juxtamembrane Region of Flt3 with Opposing Effects on Flt3-Ligand-Induced Signaling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2289-2289
Author(s):  
Lars Ronnstrand ◽  
Elke Heiss ◽  
Christina Sundberg ◽  
Kristina Masson ◽  
Malin Pedersen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Src Family Kinases ◽  
Phosphorylation Sites ◽  
Flt3 Ligand ◽  
Erk Activation ◽  
Juxtamembrane Region ◽  
Signal Relay

Abstract Early signal relay steps upon ligand-binding to the receptor tyrosine kinase Flt3, i.e. sites of Flt3-autophosphorylation and subsequent docking partners, are mainly unresolved. Here we demonstrate for the first time identification of ligand-induced in vivo phosphorylation sites in Flt3. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region of human Flt3 and subsequent radiosequencing we identified the tyrosine residues 572, 589, 591 and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we examined Flt3-ligand-mediated responses in WT-Flt3, Y589F-Flt3 and Y599F-Flt3 expressing 32D cells. Compared to WT-Flt3-32D cells, 32D-Y589F-Flt3 showed upon ligand-stimulation enhanced Erk activation as well as proliferation/survival whereas 32D-Y599F-Flt3 cells displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for multiple signal relay molecules including Src family kinases. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed decreased FL-triggered Src activation, impaired phosphorylation of the adapter molecules Cbl and ShcA and deficient receptor ubiquitination and degradation. Interference with the Src-dependent negative regulation of Flt3 signaling may account for the enhanced mitogenic response of Y589F-Flt3. pY599 was additionally found to interact with the protein tyrosine phosphatase Shp2. As Y599F-Flt3-32D lacked ligand-induced Shp2 phosphorylation and since silencing of Shp2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3-phenotype we hypothesize that recruitment of Shp2 to pY599 contributes to FL-mediated Erk activation and proliferation. To summarize, our work presents novel insights in Flt3-mediated signal transduction. We have identified the in vivo autophosphorylation sites of the juxtamembrane region of Flt3, revealed Src family kinases and Shp2 as binding partners of pY589 and/or pY599, respectively, as well as their potential impact on FL-mediated signaling in Flt3-32D cells. Future work will now focus on elucidation of additional and possibly novel interaction partners of the found phosphorylation sites by employing an unbiased proteomics approach. With this gained knowledge it will be of interest to see whether ITDs differing in the nature of the duplicated tyrosines also confer distinct signaling behavior. If so, these tyrosines might serve as a diagnostic marker and point towards a successful combinatorial therapy consisting of a receptor tyrosine kinase inhibitor and an inhibitor for the specifically affected signal transduction pathway.

Abstract 143: Catalase, Oxidative Stress and Ischemic Injury: Role of c-Abl Tyrosine Kinase

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
E Bernadette Cabigas ◽  
Guoliang Ding ◽  
Tao Chen ◽  
Talib Saafir ◽  
Mary Wagner ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Catalase Activity ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Therapeutic Interventions ◽  
Low Cardiac Output ◽  
Abl Tyrosine Kinase ◽  
Kinase C ◽  
Whole Heart

Thousands of children with congenital heart disease are subjected to corrective surgery which involves stopping the heart and exposing it to ischemia reperfusion (IR) injury. Complications after cardiopulmonary bypass like low cardiac output can lead to inadequate organ perfusion and eventual organ dysfunction if not corrected in a timely manner. Newborn (2-4 days) hearts are more susceptible to ischemic injury than adult (>8 weeks) hearts as evidenced by their diminished ability to scavenge reactive oxygen species (ROS), specifically hydrogen peroxide (H 2 O 2 ). Not only do newborn hearts exhibit decreased scavenging capability (compared to the adult) but they also contain reduced baseline levels of catalase (3.8 + 1.1 U/mg tissue in the LV and 4.3 + 2.3 U/mg tissue in the RV vs. 11.2 + 1.0 U/mg tissue in the adult LV and 11.6 + 0.3 U/mg tissue in the adult RV). We observed significantly increased levels of H 2 O 2 in newborn rabbit myocytes following IR injury (4.3-fold vs 2.2 fold; p<0.05) that was not accompanied by an increase in catalase activity as was seen in the adult myocytes. The tyrosine kinase c-Abl was shown to play a role in regulating phosphyorylation (and activation) of catalase and we hypothesized this pathway may be dysregulated in newborns, leading to differences in catalase activity. We performed immunoprecipitation with c-Abl and catalase as well as Western analysis of whole heart homogenates in both newborn and adult samples (n=3). Results demonstrated an increase in catalase phosphorylation in adult but not newborn hearts after IR. In the newborn, preliminary studies displayed diminished phosphorylation of c-Abl, indicating a potential mechanism. In addition, catalase levels seem to acutely rise following IR, too early for new protein synthesis. Catalase is known to undergo ubiquitination following release from the c-Abl complex and this may play a role in the failure of newborns to increase catalase. Elucidation of this pathway will lead to a greater understanding of the mechanisms controlling catalase activity in the newborn versus the adult heart and will prove beneficial in developing therapeutic interventions to minimize damage following ischemic injury in newborns.

scholarly journals Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

PLoS Biology ◽  
2017 ◽  
Vol 15 (7) ◽  
pp. e2002457 ◽  
Author(s):  
Kenji Hanamura ◽  
Halley R. Washburn ◽  
Sean I. Sheffler-Collins ◽  
Nan L. Xia ◽  
Nathan Henderson ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nmda Receptors ◽  
Receptor Tyrosine Kinase ◽  
Synaptic Localization ◽  
Pathological Pain

scholarly journals Study of the Role of the Tyrosine Kinase Receptor MerTK in the Development of Kidney Ischemia-Reperfusion Injury in RCS Rats

2021 ◽  
Vol 22 (22) ◽  
pp. 12103
Author(s):  
Thomas Pelé ◽  
Sebastien Giraud ◽  
Sandrine Joffrion ◽  
Virginie Ameteau ◽  
Adriana Delwail ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Annexin V ◽  
Experimental Models ◽  
Tyrosine Kinase Receptor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Major Player

Renal ischaemia reperfusion (I/R) triggers a cascade of events including oxidative stress, apoptotic body and microparticle (MP) formation as well as an acute inflammatory process that may contribute to organ failure. Macrophages are recruited to phagocytose cell debris and MPs. The tyrosine kinase receptor MerTK is a major player in the phagocytosis process. Experimental models of renal I/R events are of major importance for identifying I/R key players and for elaborating novel therapeutical approaches. A major aim of our study was to investigate possible involvement of MerTK in renal I/R. We performed our study on both natural mutant rats for MerTK (referred to as RCS) and on wild type rats referred to as WT. I/R was established by of bilateral clamping of the renal pedicles for 30′ followed by three days of reperfusion. Plasma samples were analysed for creatinine, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels and for MPs. Kidney tissue damage and CD68-positive cell requirement were analysed by histochemistry. monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and histone 3A (H3A) levels in kidney tissue lysates were analysed by western blotting. The phagocytic activity of blood-isolated monocytes collected from RCS or WT towards annexin-V positive bodies derived from cultured renal cell was assessed by fluorescence-activated single cell sorting (FACS) and confocal microscopy analyses. The renal I/R model for RCS rat described for the first time here paves the way for further investigations of MerTK-dependent events in renal tissue injury and repair mechanisms.

scholarly journals Correction: Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001452
Author(s):  
Kenji Hanamura ◽  
Halley R. Washburn ◽  
Sean I. Sheffler-Collins ◽  
Nan L. Xia ◽  
Nathan Henderson ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nmda Receptors ◽  
Receptor Tyrosine Kinase ◽  
Synaptic Localization ◽  
Pathological Pain
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