FAK family kinases in brain health and disease

Abstract

Brain disorders are now identified as one of the largest and costliest health risks throughout human life. While most brain disorders are not life threatening per se, their chronic and incurable nature renders the overall burden from these disorders much greater than would be suggested by mortality figures alone. Several neurodevelopmental conditions, including autism and dyslexia, are being diagnosed at increasing rates throughout the last few decades. Adolescence is now well recognized as a vulnerable brain developmental phase, in which mental disorders such as schizophrenia, depression, and bipolar disorder first appear. Additionally, the constant increase in life expectancy has led to a significant rise in the risk of several neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). A primary research goal of neuroscience is to decipher the molecular mechanisms that play direct roles in the pathophysiology of brain disorders, including those of the young and old alike. Research into these mechanisms will have the most significant impact on brain diseases and mental health. The focal adhesion kinase (FAK) and its homologous FAK-related proline-rich tyrosine kinase 2 (Pyk2) define a distinct family of non-receptor tyrosine kinases that are predominantly expressed in the developing as well as in the adult brain. Despite their high similarity, they are believed to fulfill distinct roles within the brain, which are partially determined by their different expression patterns, localization, and interacting proteins. Here, we provide a comprehensive and up-to-date overview of all known neuronal interactors and signaling pathways in which Pyk2 and FAK are involved. Using bioinformatics analysis and statistical tools, we validate, for the first time, the long-term hypothesis by which FAK is involved in axonal guidance and neurodevelopmental signaling, while Pyk2 has a more prominent role in functions of the adult brain, such as memory and learning. We also characterize two new and previously unidentified roles of Pyk2 in neuropathic pain signaling and neuroinflammation. Correlation of the most significant pathways for each kinase with human brain disorders revealed the involvement of Pyk2 in neurodegenerative diseases such as PD, AD, Huntington's disease (HD), and schizophrenia, while FAK was found to be mostly related to neurodevelopmental disorders in which axonal guidance plays a major role, and to a lesser extent to amyotrophic lateral sclerosis (ALS), schizophrenia, mood disorders, and AD. The involvement of FAK in these non-developmental pathways may suggest its possible role in compensating for Pyk2 in specific processes and/or brain disorders. Understanding the molecular mechanisms underlying regulation of FAK family proteins in brain and behavior may lead to novel therapeutic approaches for preventing or treating the underlying causes of neurodevelopmental abnormalities, psychiatric disorders, and neurodegenerative diseases.

Pyk2 Stabilizes Striatal Medium Spiny Neuron Structure and Striatal-Dependent Action

“…In this report, de Pins et al used 4-month-old mice. As reported by these authors in previous publications, and also discussed by our group in two recent publications [13,38], a compensatory effect of the closely related FAK may begin in older age and take over the regulation of neuronal morphology.…”

“…Pyk2 and FAK comprise the FAK family of non-receptor tyrosine kinases and share 48% amino acid sequence identity and common phosphorylation sites and similar domain structures. Despite these similarities, their expression patterns differ (reviewed in [ 13 ]). Firstly, FAK is expressed in most cells, while Pyk2 is more restricted to the central nervous system and hematopoietic cells.…”

“…Proline-rich tyrosine kinase 2 (Pyk2) is a nonreceptor tyrosine kinase highly expressed in the brain, where it is enriched in asymmetric (presumably excitatory) synapses, relative to symmetric (presumably inhibitory) synapses [ 12 ]. With regard to Pyk2, it is activated by Ca 2+ , integrin receptors, and growth factors, triggering dimer assembly and autophosphorylation, and providing a binding site for Src kinase (reviewed in [ 13 ]). Src then phosphorylates additional sites on Pyk2, which allows for the full activation of Pyk2 and its binding of downstream cytoskeletal regulatory proteins.…”

Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network

“…Focal adhesion kinases (FAK) and related proline rich tyrosine kinase 2 (Pyk2) comprise a family of non-receptor tyrosine kinases characterized by high sequence identity, conserved phosphorylation sites, and similar domain structures [123]. FAKs reside in the cytoplasm and are expressed in ubiquitous tissues, exerting essential roles in embryonic development and in human diseases such as cancer [124].…”

Fyn Signaling in Ischemia-Reperfusion Injury: Potential and Therapeutic Implications

“…Activated Fyn can also phosphorylate the nonreceptor tyrosine kinase Proline-rich tyrosine kinase 2 (proline-rich tyrosine kinase 2, Pyk2, also known as PTK2B and FAK2) [ 36 ]. It has a certain relationship with the change of intracellular calcium ion concentration and can be activated through a calcium-dependent mechanism and participate in the downstream signal transmission of Ca 2+ [ 37 ].…”