Disease relevance of Fyn

• Association between Fyn and NR2A increased immediately after brain ischemia and the increase was maintained for at least 24 h during followed reperfusion, up to about 1.7-1.8-fold relative to sham-groups [1].
• The level of Src and Fyn in PSDs, but not in other subcellular fractions, was increased after ischemia [2].
• Finally, substantial reduction of the angiotensin II-stimulated activation of Fyn, Raf-1, ERK, and expression of c-Fos by pertussis toxin pretreatment argues that G proteins of the Gi family as well as the Gq family are involved in angiotensin II-mediated mitogenic pathways in WB cells [3].
• Infection of primary oligodendrocyte cultures with recombinant adenovirus revealed that expression of Fyn or its downstream target p190RhoGAP induced process extension [4].

High impact information on Fyn

• This study identifies a dynamic regulation of synaptic NR2B-containing NMDARs through PDZ protein-mediated stabilization and AP-2-mediated internalization that is modulated by phosphorylation by Fyn kinase [5].
• The increased tyrosine kinase activity is specific to Fyn, as other Src family members are not active in oligodendrocytes [6].
• Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase [6].
• A similar effect was observed when a dominant negative Fyn was introduced in progenitor cells [6].
• Treatment of progenitors with these compounds prevented activation of Fyn and reduced process extension and myelin membrane formation [6].

Chemical compound and disease context of Fyn

• Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia [1].
• SynGAP bound to the SH2 domains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and this interaction increased after ischemia [7].

Biological context of Fyn

• Src and Fyn have been shown to play important roles in synaptic transmission and plasticity at excitatory synapses [8].
• The authors investigated the effects of this increase on the ability of the receptor subunits to bind to the Src homology 2 (SH2) domains of Src and Fyn expressed as glutathione-S-transferase-SH2 fusion proteins [2].
• Phosphorylation of the receptor by exogenous Src and Fyn was dependent upon initial binding of the kinases to PSDs via their SH2-domains [9].
• We investigated whether Fyn is involved in the Trk-dependent signal transduction pathways of neurotrophin [10].
• The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn [11].

Anatomical context of Fyn

• To investigate whether the above processes are involved in brain ischemia-induced enhancement of NMDA receptors function, we examined the effects of transient (15 min) brain ischemia followed by reperfusion on interactions involving Fyn, NR2A and PSD95 in rat hippocampus by co-immunoprecipitation [1].
• The dual response of protein kinase Fyn to neural trauma: early induction in neurons and delayed induction in reactive astrocytes [12].
• The stimulation of neurite outgrowth and polarity formation induced by cholesterol depletion was accompanied by an enhanced localization of Fyn, a Src kinase, in the lipid rafts of hippocampal neurons [13].
• A concomitant treatment with beta-cyclodextrin and a Src family kinase inhibitor, PP2, specifically blocked axon outgrowth but not dendrite outgrowth (both of which were enhanced by beta-cyclodextrin) in hippocampal neurons, suggesting that axon outgrowth modulated by cholesterol is induced in a Fyn-dependent manner [13].
• A-770041 is a 147 nM inhibitor of Lck (1 mM ATP) and is 300-fold selective against Fyn, the other Src family kinase involved in T-cell signaling [14].

Associations of Fyn with chemical compounds

• We report here that the brain region-specific compartmentalization of Fyn kinase determines NMDA receptor sensitivity to ethanol [15].
• Exogenous Fyn kinase was shown to phosphorylate on tyrosine residue(s) of Cbl from the cerebellum in vitro [16].
• STEP(61) CS pulls down Fyn when the Tyr(420) site is phosphorylated [17].
• Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420 [17].
• Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze [11].

Physical interactions of Fyn

• We therefore tested the hypothesis that RACK1 forms a homodimer that allows the simultaneous binding of Fyn and NR2B [18].

Regulatory relationships of Fyn

• Moreover, inhibition of integrin engagement or of Fyn activation blocked activation of Rac1 and cdc42 as well as myelin basic protein expression [4].
• Here we show that extracellular matrix engagement regulates the morphology of oligodendrocytes and activates Fyn [4].
• Fyn-induced APP phosphorylation and cell surface levels of APP were potentiated in the presence of Dab1 [19].

Other interactions of Fyn

• On the contrary, all Fyn and almost all MARCKS remained in the supernatant [20].
• Fluorescence microscopy experiments showed that Fyn and Prion protein were mostly not colocalized within a single neuron [20].
• Whereas PSD-associated proline-rich tyrosine kinase 2 (PYK2) and gp145TrkB were elevated immediately after the ischemic event, increases in Src and Fyn were not apparent until 6 hours of reperfusion [21].
• Based on these results, we propose that WD40-mediated homo- and heterodimerization of RACK1 mediate the formation of a transient signaling complex that includes the NMDAR, a G protein and Fyn [18].
• NMDA receptor subunit epsilon 1 (NR2A) was also a substrate for Fyn [22].

Analytical, diagnostic and therapeutic context of Fyn

• The 15-min reperfusion after brain ischemia induced enhanced co-immunoprecipitation of PSD95, Fyn and NR2A with one another [1].
• Western blotting reveals both c-Src and Fyn in the active fractions [23].
• Concerning proteins, domains were enriched in Fyn and TAG-1, which present exclusively within this fraction at any stage of cell culture, and in GAP-43, mainly during the differentiation stage [24].
• Immunoblotting analysis showed Fyn and Lyn were present in most tissue cytosols [25].
• Angiotensin II-induced tyrosine phosphorylation of signal transducers and activators of transcription 1 is regulated by Janus-activated kinase 2 and Fyn kinases and mitogen-activated protein kinase phosphatase 1 [26].

References