Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

Abstract

Background Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. Methods Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. Results PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. Conclusions Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

Computational Analysis of Cortical Neuronal Excitotoxicity in a Large Animal Model of Neonatal Brain Injury

“…However, few if any effective pharmacological agents that attenuate neuronal damage induced by excessive glutamatergic excitation have been identi ed. Our previous work strongly indicates that the Src kinase inhibitor PP2 is an effective intervention to reduce Hx-induced excitotoxic neuronal damage in the piglet neocortex [19,50]. Our previous work also suggests that this neuronal damage is initially triggered by the activation of the Ca 2+ /CaM pathway that cascades through a series of intermediate steps, including the activation of CaMKII, CaMKK2, nuclear CaMKIV, and nally CREB.…”

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury

“…However, few if any effective pharmacological agents that attenuate neuronal damage induced by excessive glutamatergic excitation have been identified. Our previous work strongly indicates that the Src kinase inhibitor PP2 is an effective intervention to reduce Hx-induced excitotoxic neuronal damage in the piglet neocortex [ 19 , 20 ]. Our previous work also suggests that this neuronal damage is initially triggered by the activation of the Ca 2+ /CaM pathway that cascades through a series of intermediate steps, including the activation of CaMKII, CaMKK2, nuclear CaMKIV, and finally CREB.…”

“…Ca 2+ entry into the endoplasmic reticulum (ER) occurred through the SERCA pump, and movement of ER Ca 2+ into the cytoplasm occurred via RyR and IP 3 /Ca 2+ channels. The Na + /Ca 2+ exchanger (NCX) modulated Na + and Ca 2+ movement between the nucleus and the ER Src kinase sub-model, which included unphosphorylated, phosphorylated, and activated forms of Src, which also incorporated disinhibition of Src by protein tyrosine phosphatase nonreceptor type 1B (PTP-1B) [ 20 ] Simplified oxygen-ATP sub-model Simplified Ca 2+ /CaM cytoplasmic signaling cascade sub-model which included activated and non-activated forms of calcium/calmodulin (CaM), calcium/calmodulin-dependent protein kinase II (CaMKII), and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Ca 2+ /CaM nuclear signaling sub-model, which included nuclear-translocated activated and non-activated forms of Ca 2+ /CaM, CaMKII, CaMKK2, and calcium/calmodulin-dependent protein kinase IV (CaMKIV) PKC-Raf-MEK-ERK cascade, which included unphosphorylated and phosphorylated forms of protein kinase C (PKC), and the mitogen-activated protein kinases Raf, MEK, and ERK CREB-Creb binding protein (CBP) regulation of Bax transcription, which also included spliceosome processing [ 21 ]. …”

“…Src kinase sub-model, which included unphosphorylated, phosphorylated, and activated forms of Src, which also incorporated disinhibition of Src by protein tyrosine phosphatase nonreceptor type 1B (PTP-1B) [ 20 ]…”

Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review

“…In particular, these studies have shown that Src kinase is involved in numerous activated intracellular pathways during HI (Paul et al, 2001 ; Mishra et al, 2009 ; Haass and Mandelkow, 2010 ; Ittner et al, 2010 ; Delivoria-Papadopoulos et al, 2011 ; Liu and Sharp, 2011 ; Hossain et al, 2012 ; Angelis and Delivoria-Papadopoulos, 2017a , b ; Kratimenos et al, 2017 ). However, there is conflicting evidence regarding its regulatory role, which may differ depending upon brain maturation.…”