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

Abstract

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.

Spatially resolved gene regulatory and disease-related vulnerability map of the adult Macaque cortex

“…We found 33 genes (28%) showed consistent patterns in snRNA-seq and spatial transcriptomics across three cortical regions (Supplementary Fig. 13 ), including schizophrenia risk gene ARHGAP10 51 (pattern 1), important transcription factor of central nerve system RFX3 52 (pattern 1) and AD-related genes LRP1B 53 (pattern 4) and PTK2 54 (pattern 5); while other 86 genes showed consistent patterns between snRNA-seq and spatial transcriptomics mostly in two of the three cortical regions. This discrepancy of snRNA and Stereo-seq may be caused by the relatively lower gene capture in the spatial transcriptomics than snRNA-seq.…”

The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

“…Protein kinases play a vital role in biology by catalyzing the transfer of a phosphate group, onto protein substrates, at the hydroxy position of specific amino acids, modifying their activity or function ( Johnson and Lewis, 2001 ; Ardito et al, 2017 ). Deregulation of kinases and their substrates is implicated in numerous diseases, and for that reason alone kinases represent a major target class for developing novel therapeutics ( Zhou et al, 2010 ; Rebholz et al, 2013 ; Roskoski, 2015 ; Yuan et al, 2019 ; Cohen et al, 2021 ; De Pins et al, 2021 ; Roskoski, 2021 ). In the context of neurodegeneration, and for Alzheimer’s disease in particular, a number of protein kinases have been involved with relevance to different key pathways ( Flajolet et al, 2007 ; Bustos et al, 2017a ; Bustos et al, 2017b ).…”

Pyk2 Regulates MAMs and Mitochondrial Dynamics in Hippocampal Neurons

“…Pyk2 is considered to be a scaffolding protein with numerous protein interactions (reviewed in [ 33 ]). In this work, we have partially defined the Pyk2 hippocampal interactome using immunoprecipitation coupled to mass-spectrometry.…”