Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions

Abstract

Fyn is a non-receptor or cytoplasmatic tyrosine kinase (TK) belonging to the Src family kinases (SFKs) involved in multiple transduction pathways in the central nervous system (CNS) including synaptic transmission, myelination, axon guidance, and oligodendrocyte formation. Almost one hundred years after the original description of Fyn, this protein continues to attract extreme interest because of its multiplicity of actions in the molecular signaling pathways underlying neurodevelopmental as well as neuropathologic events. This review highlights and summarizes the most relevant recent findings pertinent to the role that Fyn exerts in the brain, emphasizing aspects related to neurodevelopment and synaptic plasticity. Fyn is a common factor in healthy and diseased brains that targets different proteins and shapes different transduction signals according to the neurological conditions. We will primarily focus on Fyn-mediated signaling pathways involved in neuronal differentiation and plasticity that have been subjected to considerable attention lately, opening the fascinating scenario to target Fyn TK for the development of potential therapeutic interventions for the treatment of CNS injuries and certain neurodegenerative disorders like Alzheimer’s disease.

Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue

“…The increase in APP Tyr phosphorylation was analysed with respect to the basal APP expression levels in the total lysate of each sample ( Figure 1 , Figure 2 , Figure 3 and Figure 4 ). In addition, the Fyn Tyr 420 phosphorylation was also assessed as an indirect measure of Fyn TK activity [ 13 ], and the results were normalised on Fyn basal expression levels ( Figure 1 , Figure 2 , Figure 3 and Figure 4 ).…”

“…We previously showed the potential role of APP Tyr 682 phosphorylation as a biomarker for APP dysregulation in trafficking and processing, and as a predictive factor for the increased production of neurotoxic Aβ peptide and neurodegenerative processes [ 2 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 13 , 15 ]. Indeed, the dysregulation of kinase activity has been associated with the progression of other neurodegenerative diseases, and has been proposed as a potential biomarker for other major proteinopathies besides AD, including PD [ 16 , 17 , 18 ] and Huntington’s disease [ 19 , 20 ].…”

“…It is well established that Fyn can play a dual role in both the Aβ and tau pathologies observed in AD [ 21 ], exacerbating Aβ neurotoxicity through cellular prion protein (PrP C ) and interacting directly with tau [ 22 ] by phosphorylating it at Tyr 18 [ 23 ]. We previously delineated a new possible mechanism in which Fyn initiated the amyloid cascade by phosphorylating the APP Tyr 682 residue, which would then induce the amyloidogenic cleavage [ 2 , 13 ]. This cascade of events would amplify the neurotoxic effects of Aβ, tau hyperphosphorylation, neuronal tangles, and, consequently, neuronal damage.…”

Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

“…Fyn has a complex molecular structure that consists of a unique N-terminal sequence and three protein modules: Src-homology-3 (SH3) module (an interaction domain that is specialized for the recognition of xPxxP sequence motifs), Src-homology-2 (SH2) module, which recognizes pTyr, and the catalytic domain, which binds and cleaves adenosine triphosphate and mediates Tyr phosphorylation in protein targets. Intramolecular interactions that involve the SH3 and SH2 domains contribute to the negative regulation of Fyn kinase activity [36,[54][55][56][57][58][59].…”

Identification of Crucial Methylation Genes Associated With Immune Cell Infiltration in Twin-to-twin Transfusion Syndrome Using Co-methylation Analysis

“…FYN is primarily in several transduction pathways in the central nervous system, such as axon guidance, myelination, and oligodendrocytes formation. FYN regulates mechanisms related to learning and memory processes and is attributed to the development of several neurological disorders including Alzheimer's disease and multiple sclerosis [32]. Grant et al found that fyn mutant mice showed impaired spatial learning, which further illustrates that FYN may involve the core process of the growth of neurons in the developing hippocampus [33].…”