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Gene Review

Fyn  -  FYN proto-oncogene, Src family tyrosine...

Rattus norvegicus

Synonyms: Proto-oncogene c-Fyn, Tyrosine-protein kinase Fyn, p59-Fyn
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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


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


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


  1. Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia. Hou, X.Y., Zhang, G.Y., Yan, J.Z., Chen, M., Liu, Y. Brain Res. (2002) [Pubmed]
  2. The effect of transient global ischemia on the interaction of Src and Fyn with the N-methyl-D-aspartate receptor and postsynaptic densities: possible involvement of Src homology 2 domains. Takagi, N., Cheung, H.H., Bissoon, N., Teves, L., Wallace, M.C., Gurd, J.W. J. Cereb. Blood Flow Metab. (1999) [Pubmed]
  3. Angiotensin II induces diverse signal transduction pathways via both Gq and Gi proteins in liver epithelial cells. Tsygankova, O.M., Peng, M., Maloney, J.A., Hopkins, N., Williamson, J.R. J. Cell. Biochem. (1998) [Pubmed]
  4. Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes. Liang, X., Draghi, N.A., Resh, M.D. J. Neurosci. (2004) [Pubmed]
  5. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Prybylowski, K., Chang, K., Sans, N., Kan, L., Vicini, S., Wenthold, R.J. Neuron (2005) [Pubmed]
  6. Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. Osterhout, D.J., Wolven, A., Wolf, R.M., Resh, M.D., Chao, M.V. J. Cell Biol. (1999) [Pubmed]
  7. Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. Pei, L., Teves, R.L., Wallace, M.C., Gurd, J.W. J. Cereb. Blood Flow Metab. (2001) [Pubmed]
  8. Interactions between Src family protein tyrosine kinases and PSD-95. Kalia, L.V., Salter, M.W. Neuropharmacology (2003) [Pubmed]
  9. Tyrosine phosphorylation of the N-methyl-D-aspartate receptor by exogenous and postsynaptic density-associated Src-family kinases. Cheung, H.H., Gurd, J.W. J. Neurochem. (2001) [Pubmed]
  10. Association of the Src family tyrosine kinase Fyn with TrkB. Iwasaki, Y., Gay, B., Wada, K., Koizumi, S. J. Neurochem. (1998) [Pubmed]
  11. Involvement of BDNF receptor TrkB in spatial memory formation. Mizuno, M., Yamada, K., He, J., Nakajima, A., Nabeshima, T. Learn. Mem. (2003) [Pubmed]
  12. The dual response of protein kinase Fyn to neural trauma: early induction in neurons and delayed induction in reactive astrocytes. Chun, J.T., Crispino, M., Tocco, G. Exp. Neurol. (2004) [Pubmed]
  13. Cholesterol-mediated neurite outgrowth is differently regulated between cortical and hippocampal neurons. Ko, M., Zou, K., Minagawa, H., Yu, W., Gong, J.S., Yanagisawa, K., Michikawa, M. J. Biol. Chem. (2005) [Pubmed]
  14. A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejection. Stachlewitz, R.F., Hart, M.A., Bettencourt, B., Kebede, T., Schwartz, A., Ratnofsky, S.E., Calderwood, D.J., Waegell, W.O., Hirst, G.C. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  15. Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol. Yaka, R., Phamluong, K., Ron, D. J. Neurosci. (2003) [Pubmed]
  16. Phosphorylation of c-Cbl protooncogene product following ethanol administration in rat cerebellum: possible involvement of Fyn kinase. Nishio, H., Otsuka, M., Kinoshita, S., Tokuoka, T., Nakajima, M., Noda, Y., Fukuyama, Y., Suzuki, K. Brain Res. (2002) [Pubmed]
  17. Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420. Nguyen, T.H., Liu, J., Lombroso, P.J. J. Biol. Chem. (2002) [Pubmed]
  18. Spatial and temporal regulation of RACK1 function and N-methyl-D-aspartate receptor activity through WD40 motif-mediated dimerization. Thornton, C., Tang, K.C., Phamluong, K., Luong, K., Vagts, A., Nikanjam, D., Yaka, R., Ron, D. J. Biol. Chem. (2004) [Pubmed]
  19. Fyn modulation of Dab1 effects on amyloid precursor protein and ApoE receptor 2 processing. Hoe, H.S., Minami, S.S., Makarova, A., Lee, J., Hyman, B.T., Matsuoka, Y., Rebeck, G.W. J. Biol. Chem. (2008) [Pubmed]
  20. Immunoseparation of Prion protein-enriched domains from other detergent-resistant membrane fractions, isolated from neuronal cells. Botto, L., Masserini, M., Cassetti, A., Palestini, P. FEBS Lett. (2004) [Pubmed]
  21. Altered association of protein tyrosine kinases with postsynaptic densities after transient cerebral ischemia in the rat brain. Cheung, H.H., Takagi, N., Teves, L., Logan, R., Wallace, M.C., Gurd, J.W. J. Cereb. Blood Flow Metab. (2000) [Pubmed]
  22. NMDA receptor subunits epsilon 1 (NR2A) and epsilon 2 (NR2B) are substrates for Fyn in the postsynaptic density fraction isolated from the rat brain. Suzuki, T., Okumura-Noji, K. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  23. Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. Kinnunen, T., Kaksonen, M., Saarinen, J., Kalkkinen, N., Peng, H.B., Rauvala, H. J. Biol. Chem. (1998) [Pubmed]
  24. Developmental changes in the protein composition of sphingolipid- and cholesterol-enriched membrane domains of rat cerebellar granule cells. Palestini, P., Botto, L., Guzzi, F., Calvi, C., Ravasi, D., Masserini, M., Pitto, M. J. Neurosci. Res. (2002) [Pubmed]
  25. Non-receptor cytosolic protein tyrosine kinases from various rat tissues. Elberg, G., Li, J., Leibovitch, A., Shechter, Y. Biochim. Biophys. Acta (1995) [Pubmed]
  26. 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. Venema, R.C., Venema, V.J., Eaton, D.C., Marrero, M.B. J. Biol. Chem. (1998) [Pubmed]
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