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  1. Article ; Online: Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

    Vidyasiri Vemulapalli / Lily A Chylek / Alison Erickson / Anamarija Pfeiffer / Khal-Hentz Gabriel / Jonathan LaRochelle / Kartik Subramanian / Ruili Cao / Kimberley Stegmaier / Morvarid Mohseni / Matthew J LaMarche / Michael G Acker / Peter K Sorger / Steven P Gygi / Stephen C Blacklow

    eLife, Vol

    2021  Volume 10

    Abstract: SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet is frequently mutated in human cancer. Here, we examine the role of SHP2 in the responses of breast ... ...

    Abstract SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet is frequently mutated in human cancer. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by SHP099. The dynamics of phosphotyrosine abundance at more than 400 tyrosine residues reveal six distinct response signatures following SHP099 treatment and washout. Remarkably, in addition to newly identified substrate sites on proteins such as occludin, ARHGAP35, and PLCγ2, another class of sites shows reduced phosphotyrosine abundance upon SHP2 inhibition. Sites of decreased phospho-abundance are enriched on proteins with two nearby phosphotyrosine residues, which can be directly protected from dephosphorylation by the paired SH2 domains of SHP2 itself. These findings highlight the distinct roles of the scaffolding and catalytic activities of SHP2 in effecting a transmembrane signaling response.
    Keywords signal transduction ; mass spectrometry ; PTPN11 ; epidermal growth factor receptor ; phosphatase ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

    Changjun Yang / Bianca P. Lavayen / Lei Liu / Brian D. Sanz / Kelly M. DeMars / Jonathan Larochelle / Marjory Pompilus / Marcelo Febo / Yu-Yo Sun / Yi-Min Kuo / Mansour Mohamadzadeh / Susan A. Farr / Chia-Yi Kuan / Andrew A. Butler / Eduardo Candelario-Jalil

    Redox Biology, Vol 48, Iss , Pp 102197- (2021)

    2021  

    Abstract: Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain ... ...

    Abstract Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.
    Keywords Adropin ; Permanent middle cerebral artery occlusion ; Ischemic stroke ; Blood-brain barrier ; Neurovascular unit ; Neurobehavioral tests ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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