Alternative titles; symbols
HGNC Approved Gene Symbol: FYN
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:111,660,332-111,873,452 (from NCBI)
By screening a genomic library with a YES1 (164880) gene probe, Semba et al. (1986) identified a related gene, which they called SYN (src/yes-related novel gene). Northern blot analysis revealed that the 2.8-kb SYN mRNA was expressed in various cell types. The tyrosine kinase domain of the predicted 537-amino acid SYN protein is 77 to 80% identical to those of the YES1, FGR (164940), and chicken SRC (190090) tyrosine kinase oncogenes. Therefore, Semba et al. (1986) concluded that SYN is a new member of the tyrosine kinase oncogene family.
PrPc, the cellular, nonpathogenic isoform of prion protein (Prp; 176640), is a ubiquitous glycoprotein expressed strongly in neurons. Mouillet-Richard et al. (2000) used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated crosslinking. The 1C11 clone is a committed neuroectodermal progenitor with an epithelial morphology that lacks neuron-associated functions. Upon induction, 1C11 cells develop a neural-like morphology, and may differentiate either into serotonergic or noradrenergic cells. The choice between the 2 differentiation pathways depends on the set of inducers used. Ligation of PrPc with specific antibodies induced a marked decrease in the phosphorylation level of the tyrosine kinase FYN in both serotonergic and noradrenergic cells. The coupling of PrPc to FYN was dependent upon caveolin-1 (601047). Mouillet-Richard et al. (2000) suggested that clathrin (see 118960) might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent FYN activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Mouillet-Richard et al. (2000) suggested that PrPc may be a signal transduction protein.
Parravicini et al. (2002) noted that Lyn (165120) deficiency impairs some mast cell functions, but degranulation and cytokine production are intact. In Gab2 (606203)-deficient mice, on the other hand, degranulation and cytokine production are impaired. Using immunoblot analysis, they showed that although Lyn is essential for Syk (600085) activation and Lat (602354) phosphorylation after Fcer1 (see FCER1G; 147139) aggregation, neither Lyn nor Lat are necessary for Gab2 phosphorylation. RT-PCR and coimmunoprecipitation analyses demonstrated abundant Fyn expression in mast cells and an association with Gab2. In cells lacking Fyn, neither Gab2 nor Akt (164730) were phosphorylated. Functional analysis showed that Lyn -/- mast cells exhibited hyperdegranulation and enhanced PI3K (see 601232) activity and Akt phosphorylation, whereas in Fyn -/- mast cells the degranulation response was inhibited. The inhibition was associated with decreased binding of PI3K with Gab2. Parravicini et al. (2002) observed that the degranulation response was independent of Fcer1 stimulation in Fyn-deficient mast cells and that degranulation was dependent on PI3K in wildtype and mutant cell lines. The degranulation response was dependent on a rise in intracellular calcium that was inhibited in Lyn-deficient mast cells but intact in Fyn-deficient cells. Degranulation proceeded in Lyn -/- cells due to increased activation and constitutive phosphorylation of the calcium-independent protein kinase C delta isoform (PRKCD; 176977). Parravicini et al. (2002) concluded that Fyn- and Lyn-initiated pathways synergize in late events at the level of protein kinase C and calcium, respectively, to regulate mast cell degranulation.
Using yeast 2-hybrid, immunoblot, and structural analyses, Chan et al. (2003) showed that the SH2 domain of SAP (SH2D1A; 300490) bound to the SH3 domain of FYN in a noncanonical manner and directly coupled FYN to SLAM (SLAMF1; 603492).
Netrin-1 (601614) plays a role in the developing nervous system by promoting both axonal outgrowth and axonal guidance in pathfinding. Liu et al. (2004), Li et al. (2004), and Ren et al. (2004) simultaneously reported a complex network of intracellular signaling downstream from netrin-1 involving DCC (120470), focal adhesion kinase (FAK; 600758), and FYN. In neurons cultured from rat cerebral cortex, Liu et al. (2004) found that netrin-1 induced tyrosine phosphorylation of FAK and FYN, and coimmunoprecipitation studies showed direct interaction of FAK and FYN with DCC. Inhibition of FYN inhibited FAK phosphorylation, and FYN mutants inhibited the attractive turning responses to netrin. Neurons lacking the FAK gene showed reduced axonal outgrowth and attractive turning responses to netrin. In cultured neurons from chick and mouse, Li et al. (2004) found that netrin increased tyrosine phosphorylation of DCC and FAK. Coimmunoprecipitation studies showed that DCC interacted directly with FAK and SRC to form a complex and that FAK and SRC cooperated to stimulate DCC phosphorylation by SRC. Li et al. (2004) suggested that phosphorylated DCC acts as a kinase-coupled receptor and that FAK and SRC act downstream of DCC in netrin signaling. Ren et al. (2004) found that inhibition of FAK phosphorylation inhibited netrin-1-induced axonal outgrowth and guidance. The authors suggested that FAK may also function as a scaffolding protein and play a role in cytoskeletal reorganization that is necessary for neurite outgrowth and turning.
Using purified recombinant proteins, Panicker et al. (2019) showed that human FYN and CD36 (173510) mediated alpha-synuclein (SNCA; 163890) uptake in microglia. Immunohistochemical analysis revealed increased microgliosis and increased FYN expression and activation within microglia in brains of alpha-synuclein-overexpressing mice and in patients with Parkinson disease (PD; see 168601). Uptake of alpha-synuclein in microglia induced mitochondrial dysfunction and generation of mitochondrial reactive oxygen species. Aggregated alpha-synuclein primed and activated the NLRP3 (606416) inflammasome through PKC-delta (PRKCD; 176977)-mediated NF-kappa-B (see 164011) activation, resulting in diminished production of IL1-beta (IL1B1; 147720) and other proinflammatory cytokines. The authors validated the in vitro findings in a mouse model of PD, as Fyn contributed to microgliosis and microglial inflammasome activation in vivo.
Semba et al. (1986) assigned the SYN gene to chromosome 6 by analysis of somatic cell hybrids. Popescu et al. (1987) mapped the FYN gene to 6q21 by use of in situ hybridization. Boyle et al. (1992) confirmed the assignment to the proximal part of 6q21 by study of a panel of 13 hybrid cell lines containing various fragments of chromosome 6. Using a single interspecific backcross, Justice et al. (1990) demonstrated the location of the Fyn gene in relation to other genes on mouse chromosome 10.
Grant et al. (1992) found that mice homozygous for a fyn null mutation had impaired long-term potentiation and spatial learning. Yagi et al. (1993) generated fyn-deficient mice by inserting the lacZ gene into the fyn gene. Homozygous mutant mice appeared normal. However, the homozygous fyn mutant neonates from homozygous fyn mutant parents died because of a suckling problem. The mutant neonates suckled normally when the fyn mutant mothers' mammary glands had been activated by suckling of a heterozygous or wildtype pup. In homozygous mutant pups, the modified glomerular complex of the olfactory bulb, thought to be involved in pheromone perception, was abnormally shaped and reduced in size and the hippocampal cell-layer was undulated. Since suckling is mediated by pheromones, Yagi et al. (1993) speculated that the suckling problem might be due to altered pheromone sensitivity. Yagi et al. (1993) noted that Grant et al. (1992) did not observe a suckling defect in fyn mutant mice. Yagi et al. (1993) suggested that this might be due to the fact that the mice with a suckling defect had an insertional mutation in fyn, while Grant et al. (1992) were studying mice with a null allele.
Cain et al. (1995) studied electrical kindling in mice containing a null mutation in the fyn tyrosine kinase gene. Electrical kindling is achieved by applying brief low intensity electrical stimuli over a period of days to the brain, resulting in an electrical seizure focus that may persist for months to years. The fyn mutants showed a striking retardation in the rate of kindling, even though the phenomenon crucial for kindling (i.e., the threshold duration and stability of epileptiform after discharges) were normal. This implied to the authors that function of the fyn gene is required for normal epileptogenesis.
SYK controls pre-B cell development but does not affect NFKB induction. Saijo et al. (2003) showed that mice triple-deficient in the Src family protein tyrosine kinases (SFKs) Blk (191305), Fyn, and Lyn, but not single-deficient or Syk-deficient mice, had impaired Nfkb induction and B-cell development. The impairment of Nfkb induction could be overcome by protein kinase C-lambda (see 176982) activation. Saijo et al. (2003) suggested that there are 2 separate pathways in pre-B cell receptor signaling, one SFK-dependent and the other SYK-dependent, that contribute critically to pre-B cell development.
Boyle, J. M., Hey, Y., Myers, K., Stern, P. L., Grzeschik, F.-H., Ikehara, Y., Misumi, Y., Fox, M. Regional localization of a trophoblast antigen-related sequence and 16 other sequences to human chromosome 6q using somatic cell hybrids. Genomics 12: 693-698, 1992. [PubMed: 1572643] [Full Text: https://doi.org/10.1016/0888-7543(92)90296-5]
Cain, D. P., Grant, S. G. N., Saucier, D., Hargreaves, E. L., Kandel, E. R. Fyn tyrosine kinase is required for normal amygdala kindling. Epilepsy Res. 22: 107-114, 1995. [PubMed: 8777897] [Full Text: https://doi.org/10.1016/0920-1211(95)00029-1]
Chan, B., Lanyi, A., Song, H. K., Griesbach, J., Simarro-Grande, M., Poy, F., Howie, D., Sumegi, J., Terhorst, C., Eck, M. J. SAP couples Fyn to SLAM immune receptors. Nature Cell Biol. 5: 155-160, 2003. [PubMed: 12545174] [Full Text: https://doi.org/10.1038/ncb920]
Grant, S. G. N., O'Dell, T. J., Karl, K. A., Stein, P. L., Soriano, P., Kandel, E. R. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258: 1903-1910, 1992. [PubMed: 1361685] [Full Text: https://doi.org/10.1126/science.1361685]
Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866, 1990. [PubMed: 1975791] [Full Text: https://doi.org/10.1093/genetics/125.4.855]
Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nature Neurosci. 7: 1213-1221, 2004. [PubMed: 15494734] [Full Text: https://doi.org/10.1038/nn1329]
Liu, G., Beggs, H., Jurgensen, C., Park, H.-T., Tang, H., Gorski, J., Jones, K. R., Reichardt, L. F., Wu, J., Rao, Y. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nature Neurosci. 7: 1222-1232, 2004. [PubMed: 15494732] [Full Text: https://doi.org/10.1038/nn1331]
Mouillet-Richard, S., Ermonval, M., Chebassier, C., Laplanche, J. L., Lehmann, S., Launay, J. M., Kellermann, O. Signal transduction through prion protein. Science 289: 1925-1928, 2000. [PubMed: 10988071] [Full Text: https://doi.org/10.1126/science.289.5486.1925]
Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M., Kam, T., Jin, H., Saminathan, M., Langley, M., Charli, A., Samidurai, M., Rokad, D., Ghaisas, S., Pletnikova, O., Dawson, V. L., Dawson, T. M., Anantharam, V., Kanthasamy, A. G., Kanthasamy, A. Fyn kinase regulates misfolded alpha-synuclein uptake and NLRP3 inflammasome activation in microglia. J. Exp. Med. 216: 1411-1430, 2019. [PubMed: 31036561] [Full Text: https://doi.org/10.1084/jem.20182191]
Parravicini, V., Gadina, M., Kovarova, M., Odom, S., Gonzalez-Espinosa, C., Furumoto, Y., Saitoh, S., Samelson, L. E., O'Shea, J. J., Rivera, J. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nature Immun. 3: 741-748, 2002. [PubMed: 12089510] [Full Text: https://doi.org/10.1038/ni817]
Popescu, N. C., Kawakami, T., Matsui, T., Robbins, K. C. Chromosomal localization of the human FYN gene. Oncogene 1: 449-451, 1987. [PubMed: 3330788]
Ren, X., Ming, G., Xie, Y., Hong, Y., Sun, D., Zhao, Z., Feng, Z., Wang, Q., Shim, S., Chen, Z., Song, H., Mei, L., Xiong, W. Focal adhesion kinase in netrin-1 signaling. Nature Neurosci. 7: 1204-1212, 2004. [PubMed: 15494733] [Full Text: https://doi.org/10.1038/nn1330]
Saijo, K., Schmedt, C., Su, I., Karasuyama, H., Lowell, C. A., Reth, M., Adachi, T., Patke, A., Santana, A., Tarakhovsky, A. Essential role of Src-family protein tyrosine kinases in NF-kappa-B activation during B cell development. Nature Immun. 4: 274-279, 2003. [PubMed: 12563261] [Full Text: https://doi.org/10.1038/ni893]
Semba, K., Nishizawa, M., Miyajima, N., Yoshida, M. C., Sukegawa, J., Yamanashi, Y., Sasaki, M., Yamamoto, T., Toyoshima, K. yes-related protooncogene, syn, belongs to the protein-tyrosine kinase family. Proc. Nat. Acad. Sci. 83: 5459-5463, 1986. [PubMed: 3526330] [Full Text: https://doi.org/10.1073/pnas.83.15.5459]
Yagi, T., Aizawa, S., Tokunaga, T., Shigetani, Y., Takeda, N., Ikawa, Y. A role for Fyn tyrosine kinase in the suckling behaviour of neonatal mice. Nature 366: 742-745, 1993. [PubMed: 8264796] [Full Text: https://doi.org/10.1038/366742a0]