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Review
. 2020 Jun 22;21(12):4444.
doi: 10.3390/ijms21124444.

Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions

Carmela Matrone  1 , Federica Petrillo  2 , Rosarita Nasso  1 , Gabriella Ferretti  1
Affiliations
Review

Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions

Carmela Matrone et al. Int J Mol Sci. .

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.

Keywords: Alzheimer’s disease; Fyn tyrosine kinase; neurodegeneration; plexins; semaphorins; synaptic plasticity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Fyn structure. The SH4 domain, is a membrane-targeting domain containing signals for the appropriate subcellular localization and membrane attachment of Fyn [21]. This domain consists of an extreme N-terminal ‘Met-Gly-Cys’ motif followed by a polar region [9,22]. The N-terminal Gly2 seems to be an absolute requirement for myristylation. Cys3 and Cys6, are both palmitoylated via a thioester linkage [23], thus, allowing Fyn anchors to the plasma membrane [24,25,26]. Between the SH4 and the SH3 motifs, there is a short region called “the unique region” that it is likely to be required for the subcellular localization of Fyn [27]. The SH3 motif constitutes a small domain of 50 amino acids containing a consensus sequence XPXXPPPXXP [28] that allows the binding to amino acid sequences rich in proline residues [29]. The SH2 domain consists of about 100 amino acids and appears to facilitate the binding to phosphotyrosine residues and to hydrophobic sequences within the cytoplasmic tails of growth factor receptors (i.e., PDGF-R, CSF-1 R) [30,31]. The catalytic domain SH1 is responsible of TK specific activity. This domain is highly conserved among Src family members [32]. The kinase domain, that catalyses the transfer of the terminal ATP phosphate group to a tyrosine residue of a target protein, shows a typical bilobed structure consisting in a small N-terminal lobe, involved in the binding with ATP, and a larger C-terminal lobe, where an activation loop (A-loop) is present. The conserved Tyr420, crucial for Src activity, is included in this domain [33]. However, the major site of phosphorylation and regulation of Fyn TK activity is the short negative regulatory tail where Tyr531 is located [32]. Adapted from Krämer-Albers et al. (2011) [34].
Figure 2
Figure 2
Fyn expression in human brain. (A) Fyn mRNA expression during development (6–20 refers to embryonic days; P7 = 7 days post-hatch). Adapted from Bixby et al. (1993) [58]. (B) Fyn human expression in the different areas of adult brain (data extracted from ATLAS).
Figure 3
Figure 3
Fyn functions in the brain. Adapted from Schenone et al. (2011) [8].
Figure 4
Figure 4
A proposed mechanism by which Fyn and Cdk5 control Sema3A and PlexinA2 downstream signaling cascade either in physiologic (left) or in pathologic (right) conditions. Fyn phosphorylates PlexinA2 and promotes PlexinA2 interaction to Sema3A. Fyn also phosphorylates cyclin-dependent kinase-5 (Cdk5) and in turn collapse response mediator protein (CRMP). The activation of Cdk5 facilitates the suppression of Rac-PAK signaling leading to the actin dynamic regulation. On the other hand, when phosphorylated, Cdk5 activates Tau resulting in destabilization of microtubules. Both these events culminate in growth cone collapse, remodeling of synaptic network and regulation of dendrites and axonal orientation (Adapted from Sasaki et al. 2002) [111].
Figure 5
Figure 5
Fyn target proteins in AD neurons. Left: When overactivated, Fyn promotes phosphorylation either of APP at Tyr682 or Tau at Tyr18. These target protein hyperphosphorylations activate downstream pathways finally resulting in AD-related neuronal dysfunction and death. Right: A proposed mechanism by which Fyn, after interacting with the Aβ oligomers-Prion like protein complex, phosphorylates NR2B receptor and triggers excitotoxicity.
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