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Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.

ABSTRACT: Proline-rich tyrosine kinase 2 (PYK2), also known as cell adhesion kinase beta or protein tyrosine kinase 2b, is a calcium-dependent signaling protein involved in cell migration. Phosphorylation of residue Y402 is associated with activation of PYK2 and leads to the recruitment of downstream signaling molecules. PYK2 was previously implicated in long-term potentiation (LTP); however, the role of PYK2 in long-term depression (LTD) is unknown. Here, we report that PYK2 is activated by NMDA receptor stimulation (chemical LTD) in cultured neurons. Small hairpin RNA-mediated knockdown of PYK2 blocks LTD, but not LTP, in hippocampal slice cultures. We find that the Y402 residue and, to a lesser extent, PYK2 kinase activity contribute to PYK2's role in LTD. Knockdown experiments indicate that PYK2 is required to suppress NMDA-induced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of PYK2 depresses NMDA-induced ERK phosphorylation and inhibits LTP, but not LTD. Our data indicate that PYK2 is critical for the induction of LTD, possibly in part by antagonizing ERK signaling in hippocampal neurons.

SUBMITTER: Hsin H

PROVIDER: S-EPMC4122232 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.

Hsin Honor H Kim Myung Jong MJ Wang Chi-Fong CF Sheng Morgan M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100901 36

Proline-rich tyrosine kinase 2 (PYK2), also known as cell adhesion kinase beta or protein tyrosine kinase 2b, is a calcium-dependent signaling protein involved in cell migration. Phosphorylation of residue Y402 is associated with activation of PYK2 and leads to the recruitment of downstream signaling molecules. PYK2 was previously implicated in long-term potentiation (LTP); however, the role of PYK2 in long-term depression (LTD) is unknown. Here, we report that PYK2 is activated by NMDA receptor ...[more]

PMID: 20826662

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Project description:BACKGROUND:The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5' cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function. METHODS:Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors. RESULTS:4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects. LIMITATIONS:This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue. CONCLUSIONS:Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD.

Project description:AimsWe previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism.Methodology/principal findingsStable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples.ConclusionsOur results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes.

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Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.

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Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression.

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