Disease relevance of Fyn

• Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice [1].
• This specific role of Fyn can be verified in SH-SY5Y human neuroblastoma cells with endogenously expressed M2 receptors [2].
• These results suggest that disruption of hemidesmosomes mediated by Fyn is a prerequisite for normal keratinocyte migration and squamous carcinoma invasion [3].
• Lymphadenopathy and other disease manifestations were greatly reduced in Fyn-/- lpr mice concomitant to decreased DN cells (from 77 to 20%) [4].
• Particularly noteworthy are the preferential binding of Fyn by HamT and the induction of lymphoid malignancies by the hamster polyomavirus [5].

Psychiatry related information on Fyn

• Decreased locomotor activity in mice carrying transgenic Fyn tyrosine kinase [6].
• Together, these results suggest that Fyn can modulate alcohol consumption and prevent behavioural changes during alcohol withdrawal, possibly via phosphorylation of NR2B [7].
• In addition, Fyn-deficient females exhibited defects in the maternal behavior of nest building and pup retrieval, regardless of exposure to hexanal [8].
• Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease [9].
• To further study the involvement of Fyn in neurobehavioral effects of alcohol, we examined ethanol consumption and relapse drinking behavior in fynZ/fynZ mice [10].

High impact information on Fyn

• Upon integrin ligation, Fyn is activated and binds, via its SH3 domain, to Shc [11].
• A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth [11].
• Cells derived from these embryos exhibit an order of magnitude increase in activity of Src and the related Fyn kinase [12].
• VEGF induction by hypoxia in c-src(-) cells is impaired, although there is a compensatory activation of Fyn [13].
• Crosslinking of large MAG with antibody induces a rapid increase in the specific activity of Fyn kinase [14].

Chemical compound and disease context of Fyn

• Unchanged scrapie pathology in brain tissue of tyrosine kinase Fyn-deficient mice [15].
• Here we show that the FcRgamma/Fyn signaling cascade is critically involved in cuprizone-induced demyelination/remyelination, with no lymphocytic response [16].
• Fyn-kinase-deficient mice are known to exhibit hypersensitivity to ethanol [17].
• These findings indicate that the tyrosine phosphorylation of the NMDA receptors by Fyn participates in the control of locomotor activity [6].

Biological context of Fyn

• The Fyn-large MAG association requires amino-terminal domains of Fyn that include SH2 and SH3 (Src homology domains 2 and 3) [14].
• The phenotype of the Itk/Fyn doubly deficient mice was similar to that of Itk deficient mice [18].
• The interaction between tr-kit and Fyn triggers activation of the kinase as monitored by both autophosphorylation and phosphorylation of PLCgamma1 [19].
• Fyn tyrosine protein kinase is a potential mediator in T-cell antigen receptor signal transduction in subsets of T cells [20].
• Using SinDeltaC and fyn(-/-) animals, we also found that the expression of Fyn was required for the inhibitory effect of SinDeltaC on thymocyte apoptosis but not for SinDeltaC-mediated inhibition of T cell maturation [21].

Anatomical context of Fyn

• Here we show that the combined disruption of Lck and Fyn (lck(-/-)fyn(-/-)) completely arrests alpha beta T cell development at the CD4-CD8- stage [22].
• Fyn is localized in the cortex region underneath the plasma membrane in mouse oocytes [19].
• Finally, microinjection of constitutively active Fyn triggers oocyte activation downstream of tr-kit but still requires PLC activity [19].
• NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice [23].
• Haploinsufficiency or complete deficiency of protein kinase C beta, Fyn, CD22, Galphaq, or Galpha11 had no detectable effect on the function of Btk(lo) B cells [24].

Associations of Fyn with chemical compounds

• Initial events of myelination involve Fyn tyrosine kinase signalling [14].
• In this study, we examined how Fyn participates in synaptic plasticity by analyzing the physical and functional interaction between Fyn and NMDA receptors [25].
• Unlike the current prevailing model, Fyn-induced activation of Ras might involve the stimulation of the catalytic guanine nucleotide exchange activity of mSOS [20].
• Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility [1].
• These data suggest the unexpected conclusion that the Fyn SH2 domain may bind to Cbl in a phosphotyrosine-independent manner [26].
• Together, these data demonstrate crosstalk between Src-family kinase activity and fatty acid oxidation and show that the loss of Fyn markedly improves peripheral tissue insulin sensitivity by relieving a selective negative modulation of AMP kinase activity in adipose tissue and skeletal muscle [27].

Physical interactions of Fyn

• The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation [28].
• Kv2.1- channel subunits are found to interact with the Fyn SH2 domain [29].
• We suggest that AChRs are initially phosphorylated by Src and subsequently bind Fyn in a phosphotyrosine-dependent manner [30].
• We utilized yeast two-hybrid cloning to identify the product of the tctex-1 gene as a protein that specifically interacts with Fyn, but not with other Src family kinases [31].
• We also present the isolation and in vitro characterization of Fyn SH3-derived proteins binding to the extra-domain B of fibronectin, a marker of angiogenesis [32].

Enzymatic interactions of Fyn

• The Fyn SH2 domain bound to both tyrosine-phosphorylated and nonphosphorylated Cbl, implying that this interaction might be phosphotyrosine-independent [33].
• Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site [34].
• When fyn copy number is reduced, src, but not yes, becomes important, reflecting a partial redundancy between fyn and src.CONCLUSIONS: Reelin activates Fyn to phosphorylate and downregulate Dab1 during brain development [35].
• Thus, we propose that Fyn phosphorylates and activates ZAP-70 and that both kinases cooperate in TCR signaling [36].
• Seven out of 25 tyrosine residues in the C-terminal cytoplasmic region of GluR epsilon 2 were phosphorylated by Fyn in vitro [37].

Co-localisations of Fyn

• Finally, we have observed that after IGF-I stimulation, IGF-IR and Fyn colocalize in lipid raft caveolin 1-enriched microdomains [38].
• The Fyn tyrosine kinase colocalizes with E-cadherin at the cell membrane in calcium-treated keratinocytes [39].

Regulatory relationships of Fyn

• Protein tyrosine phosphatase alpha regulates Fyn activity and Cbp/PAG phosphorylation in thymocyte lipid rafts [40].
• The epitope-tagged Efs was hyperphosphorylated when cotransfected with a vector expressing Fyn [41].
• Thus, the NMDA-R protein level is regulated by the Reelin protein level in a Fyn-dependent manner in the mouse brain [42].
• Overexpression of Fyn mutants with an activated kinase mutation and with a Src homology 2 deletion mutation resulted in a stimulation and suppression of the mSOS activity, respectively [20].
• Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells [20].

Other interactions of Fyn

• These observations reveal that Fyn can subserve some Lck-like functions in T cell development [43].
• However the Itk/Fyn doubly deficient mice exhibited a more severe defect in TCR-induced proliferation of thymocytes and peripheral T cells than did mice deficient in either kinase alone [18].
• We show that the Src-like kinase Fyn phosphorylates Tyr161 in tr-kit and that this residue is essential for tr-kit function [19].
• We infer from these results that both Fyn and Lyn are required and that their signals are synergistic for B cell triggering after CD38 ligation [44].
• The deficiency in Vav phosphorylation in Fyn-deficient T cells was associated with a defect in the formation of APC-T cell conjugates when T cells were stimulated with either agonist or antagonist peptide [45].

Analytical, diagnostic and therapeutic context of Fyn

• Microinjection of the Src homology 2 (SH2) domain of Fyn was also inhibitory [46].
• The addition of [gamma-32P]ATP to either anti-Cbl immunoprecipitates or anti-Fyn immunoprecipitates resulted in the phosphorylation of both Cbl and Fyn as demonstrated by immunoprecipitation of the phosphorylated proteins with specific antisera [33].
• Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice [1].
• In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics [1].
• Far Western blot analysis also indicated that the SH3 domain of Fyn bound preferentially to the proline-rich region of Cbl [33].

References