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.