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Journal of Molecular and Clinical Medicine  2018, Vol. 1 Issue (3): 177-190    DOI: 10.31083/j.jmcm.2018.03.007
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FAK family kinases in brain health and disease
Kolluru D. Srikanth1, Tomer Meirson1, 2, Dev Sharan Sams3, Hava Gil-Henn1, *()
1 Laboratory for Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel
2 Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel
3 Molecular and Behavioral Neuroscience Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, 1311502, Israel
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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.

Key words:  Brain disorder      Signaling pathway      Tyrosine kinase      Pyk2      FAK      Neurodevelopmental      Neuropsychiatric      Neurodegenerative     
Submitted:  29 July 2018      Revised:  01 September 2018      Accepted:  03 September 2018      Published:  20 September 2018     
*Corresponding Author(s):  Hava Gil-Henn     E-mail:  Hava.Henn@biu.ac.il

Cite this article: 

Kolluru D. Srikanth,Tomer Meirson,Dev Sharan Sams,Hava Gil-Henn. FAK family kinases in brain health and disease. Journal of Molecular and Clinical Medicine, 2018, 1(3): 177-190.

URL: 

https://jmcm.imrpress.com/EN/10.31083/j.jmcm.2018.03.007     OR     https://jmcm.imrpress.com/EN/Y2018/V1/I3/177

Fig. 1.  Structural organization and activation mechanisms of FAK family proteins. (A) Domain structure of FAK family proteins. FAK and Pyk2 share a similar domain arrangement with 60% amino acid sequence identity within the central kinase domain, and 40% amino acid sequence identity within other protein regions, which contain three conserved proline-rich regions (PRRs), a FERM domain, and a FAT domain. In addition, the two kinases share identical positions of three tyrosine phosphorylation sites: auto-phosphorylation and Src binding site (Y397 in FAK and Y402 in Pyk2), kinase activation loop phosphorylation sites (Y576-577 in FAK and Y579-580 in Pyk2), and Grb2 binding site (Y925 in FAK and Y881 in Pyk2). (B) Activation mechanism of FAK family proteins. (1) In their inactive state, FAK/Pyk2 adopt a folded conformation. (2) Following ligand stimulation (i.e. growth factor or extracellular matrix protein), FAK/Pyk2 are unfolded and homodimerize via their FERM domains. Following dimerization and auto-phosphorylation, Src is recruited and phosphorylates the kinase activation loop in FAK/Pyk2, leading to complete activation of the kinases. (3) Src then phosphorylates additional tyrosine residues outside of the kinase domain of FAK/Pyk2. (4) Src-mediated phosphorylation and activation of FAK/Pyk2 leads to binding of downstream signaling proteins such as cortactin (Cttn), Grb2, and paxillin, which bind in the PRRs, FAT domain tyrosine, or FAT domain, respectively, and mediate downstream signaling.

Table 1  Top neuronal canonical pathways of Pyk2 and FAK and their related brain disorders.
Canonical pathway Associated disorders References
Glutamate receptor signaling Parkinson's disease Huntington's disease Alzheimer disease [51]
Neuropathic pain signaling in dorsal horn Mechanical allodynia [52]
neurons
Synaptic long-term potentiation Parkinson's disease Alzheimer's disease Huntington's disease Schizophrenia [53]
Neuroinflammation signaling pathway Multiple sclerosis Alzheimer's disease Huntington disease Parkinson's disease Autism [54]
GABA receptor signaling Autism
Alzheimer's disease Parkinson's disease Hyperactivity disorder
[55,56]
Neuroprotective role of THOP1 in Alzheimer's disease [57]
Alzheimer's disease
Parkinson's signaling Parkinson's disease [58]
Dopamine receptor signaling Parkinson's disease Huntington's disease [59]
Synaptic long-term depression Parkinson's disease Alzheimer's disease Huntington's disease [60]
Dopamine-DARPP32 feedback in cAMP signaling Schizophrenia
Obsessive-compulsive disorder
[61]
NOS signaling in neurons Alzheimer's disease Huntington's disease [62]
CREB signaling in neurons Rett syndrome Cognitive impairments [63]
Amyloid processing Alzheimer's Disease [64]
Neurotrophin/TRK signaling Alzheimer's disease Huntington's disease [65]
GDNF family ligand-receptor interactions Epilepsy
Alzheimer's disease Parkinson's disease
[66,67]
Huntington's disease signaling Huntington's disease [19]
Neuregulin signaling Alzheimer's disease Myelination [68]
Semaphorin signaling in neurons Amyotrophic lateral sclerosis Alzheimer's disease [69]
Reelin signaling in neurons Alzheimer's disease Schizophrenia Mood disorders [70,71]
Axonal guidance signaling Neuronal Development Corpus callosum dysgenesis Cystic fibrosis
Joubert syndrome and related disorders (JSRD)
[72]
Fig. 2.  Network maps of Pyk2, FAK, and their respective neuronal interacting proteins. A list of neuronal proteins that interact with Pyk2 (left), FAK (right) or both was extracted from the top corresponding neuronal canonical pathways that were obtained from IPA. The connection of Pyk2 or FAK to each protein was manually validated by using Google Scholar and PubMed search (see Supplementary Table 1). Solid lines represent direct relationship between two proteins, whereas dashed lines represent indirect relationship.

Fig. 3.  A comparative core analysis of top canonical pathways for Pyk2 and FAK. Experimentally validated phosphorylation and protein-protein interaction data were obtained from IPA and data previously published[45], from which neuronal canonical pathway enrichments for Pyk2 and FAK associated proteins was performed. The bar plot represents the difference in significance of the enriched pathways based on Pyk2 versus FAK relationships. Significance was examined using the Fisher's exact test.

Fig. 4.  Glutamate receptor signaling. Glutamate is a non-essential amino acid and a predominant excitatory neurotransmitter in the brain. In the nervous system, glutamate plays a crucial role in learning and memory of an organism. It also has a critical role in LTP and synaptic plasticity of neurons. Glutamate receptors are classified into two types: metabotropic receptors (GRM) and ionotropic receptors (GRIN). Metabotropic receptors are involved in the metabolic formation of secondary messengers whereas ionotropic receptors are ligand-gated ion channels. Ionotropic receptors are further classified into NMDA and AMPA receptors. The receptors are activated by glutamate, which results in the Na$^{+}$ ion-mediated depolarization in the neuron and development of excitatory post-synaptic potential (EPSP). Shown is a representative image from IPA depicting the pathway of glutamate receptor signaling with known Pyk2 interactions. Blue lines indicate the connection between Pyk2 and its interactors in the glutamate pathway. Other relevant interactions for this pathway, which do not connect with Pyk2 directly, are shown in gray. The connections of Pyk2 to each of the proteins were manually validated by using Google Scholar and PubMed search.

Fig. 5.  Neuropathic pain signaling in dorsal horn neurons. Neuropathic pain refers to the pain that originates from pathology of the nervous system. These pathologies may result from surgery, diabetic neuropathy, amputation, viral infection, nerve trauma and nerve compression. The most common symptom of neuropathic pain is mechanical allodynia, which is a painful sensation caused by innocuous stimuli such as light touch[46]. The pathway depicts the signaling cascade of neuropathic pain and the possible involvement of Pyk2. Blue lines indicate the known interactions between Pyk2 and other proteins involved in the pathway. Other interactions that do not involve direct interaction with Pyk2 are depicted in gray. The connections of Pyk2 to each of the proteins were manually validated by using Google Scholar and PubMed search.

Fig. 6.  Synaptic long-term potentiation (LTP). LTP is an increase in the strength of synapse between two neurons followed by high stimulation. It plays an important role in learning and memory and in synaptic plasticity. In the hippocampus, LTP induction requires the activation of post-synaptic NMDA receptors (GRIN). Ca$^{+2}$ influx through NMDA receptors results in the activation of ERK, cAMP signal transduction pathways and calcium/calmodulin-dependent protein kinase II (CamKII). Activation of these pathways induces a rapid increase in the number of AMPA receptors at the synapse. In addition to the ionotropic receptors, the metabotropic glutamate receptors (GRM) also play a role in LTP. These receptors activate, via G-protein coupled receptors (GPCRs), the phospholipase C (PLC)/protein kinase C (PKC) pathway, which triggers the NMDA receptor and thus increase Ca$^{+2 }$ influx[47,48,49]. The pathway highlights the important components of long-term potentiation and the involvement of Pyk2 in the pathway. Shown is a representative image of the pathway depicting direct interactions between Pyk2 and other proteins involved in this pathway (blue lines). Other interactions that do not involve direct interaction with Pyk2 are depicted in gray. The connections of Pyk2 to each of the proteins were manually validated by using Google Scholar and PubMed search.

Fig. 7.  (A, B), Axonal guidance signaling. Axonal guidance, also known as axon pathfinding, is a process by which growing nerve fibers find their targets in the developing brain. The axonal growth cone, located at the axon leading edge, contains receptors that sense attractive and repulsive guidance cues, which help navigate the axon to its destination. These attractive and repulsive guidance cues are guided through four major families of guidance molecules and receptors including: 1) Netrins, DCC, and UNC-5 receptors, 2) Slits and Robo receptors, 3) Semaphorins, plexin, and neurophilin receptors, and 4) Ephrins and ephrin receptors. Shown is the IPA canonical pathway of axonal guidance with known protein-FAK interactions. Red lines indicate the connection between FAK and other proteins involved in the pathway. Other relevant protein interactions for this pathway, which do not involve FAK, are shown in gray. The connections of FAK to each of the proteins were manually validated by using Google Scholar and PubMed search.

Fig. 8.  Reelin signaling in neurons. Reelin is a large extracellular glycoprotein that plays a crucial role in regulating migration of neurons and proper positioning of the cortical layers in the developing brain. In the adult brain, it assists in the maintenance of synapses and helps in the stimulation of dendrites and dendritic spines. Shown is a representative IPA canonical pathway of Reelin signaling in neurons. Red lines indicate the connection between FAK and other proteins involved in the pathway. Other relevant protein interactions for this pathway not involving FAK, are shown in gray. The connections of FAK to each of the proteins were manually validated by using Google Scholar and PubMed search.

Fig. 9.  Semaphorin signaling in neurons. Semaphorins are a large family of membrane-associated proteins that play a crucial role in the regulation of diverse developmental processes. Semaphorins are known for their ability to provide attractive or repulsive cues for migrating cells and growing neurites, i.e. dendrites and axons. One of the important downstream outputs of semaphorin signaling is actin depolymerization, which is enhanced by cytoskeletal proteins such as cofilin and PAK. Shown is a representative IPA canonical pathway of semaphorin signaling in neurons. Red lines indicate the connection between FAK and other proteins involved in the pathway. Other relevant protein interactions for this pathway not involving FAK are shown in gray. The connections of FAK to each of the proteins were manually validated by using Google Scholar and PubMed search.

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