Src Family Tyrosine Kinase Fyn Research Articles

The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor (TCR)-mediated signaling pathway, such as the lymphocyte-specific protein tyrosine kinase (Lck), Src family tyrosine kinases Fyn, and the phosphorylation levels of Zeta-chain-associated protein kinase-70 (ZAP70). For the first time, we have successfully produced PTPN22 CS transgenic mice in which the tyrosine phosphatase activity of PTPN22 is suppressed. Notably, the number of thymocytes in the PTPN22 CS mice was significantly reduced, and the expression of cytokines in the spleen and lymph nodes was changed significantly. Furthermore, PTPN22 CS facilitated the positive and negative selection of developing thymocytes, increased the expression of the TCRαβ-CD3 complex on the thymus cell surface, and regulated their internalization and recycling. ZAP70, Lck, Phospholipase C gamma1(PLCγ1), and other proteins were observed to be reduced in PTPN22 CS mouse thymocytes. In summary, PTPN22 regulates TCR internalization and recycling via the modulation of the TCR signaling pathway and affects TCR expression on the T cell surface to regulate negative and positive selection. PTPN22 affected the development of the thymus, spleen, lymph nodes, and other peripheral immune organs in mice. Our study demonstrated that PTPN22 plays a crucial role in T cell development and provides a theoretical basis for immune system construction.

Loss of tau and Fyn reduces compensatory effects of MAP2 for tau and reveals a Fyn-independent effect of tau on calcium.

Microtubule-associated protein tau associates with Src family tyrosine kinase Fyn and is tyrosine phosphorylated by Fyn. The presence of tyrosine phosphorylated tau in AD and the involvement of Fyn in AD has drawn attention to the tau-Fyn complex. In this study, a tau-Fyn double knockout (DKO) mouse was generated to investigate the role of the complex. DKO mice resembled Fyn KO in novel object recognition and contextual fear conditioning tasks and resembled tau KO mice in the pole test and protection from pentylenetetrazole-induced seizures. In glutamate-induced Ca2+ response, Fyn KO was decreased relative to WT and DKO had a greater reduction relative to Fyn KO, suggesting that tau may have a Fyn-independent role. Since tau KO resembled WT in its Ca2+ response, we investigated whether microtubule-associated protein 2 (MAP2) served to compensate for tau, since the MAP2 level was increased in tau KO but decreased in DKO mice. We found that like tau, MAP2 increased Fyn activity. Moreover, tau KO neurons had increased density of dendritic MAP2-Fyn complexes relative to WT neurons. Therefore, we hypothesize that in the tau KO, the absence of tau would be compensated by MAP2, especially in the dendrites, where tau-Fyn complexes are of critical importance. In the DKO, decreased levels of MAP2 made compensation more difficult, thus revealing the effect of tau in the Ca2+ response.

Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders.

Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results in progressive degeneration of neurons in the hippocampus and cortex and increases depression risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a promising molecular target for atypical antidepressant drugs of new generation.

Progress on Fyn-mediated phosphorylation of the N-methyl-D-aspartate receptor subtype 2B receptor in the treatment of chronic pain

Background The overactivity of N-methyl-D-aspartate (NMDA) receptors in spinal cord dorsal horn plays a critical role in central sensitization of chronic pain. Recent studies indicate that the phosphorylation of NMDA receptors(NR) are tightly regulated by the Src family tyrosine kinase Fyn, through dynamic interactions with various scaffolding proteins in the NR2B subunit of NR. Objective This article aims to further elucidate the mechanism of chronic pain, and explore novel methods for pain management. Content The article focuses on the mechanism of phosphorylation of NR mediated by Fyn, and the essential role of Fyn in the central sensitization of chronic pain. Trend Prevention of the phosphorylation of NR2B-containing NR mediated by Fyn may become a new target for the treatment of chronic pain. Key words: Fyn; N-methyl-D-aspartate receptor; Subtype 2B; Chronic pain

The Src Family Tyrosine Kinase fyn Protects Mice from Inflammation‐induced Lung Injury

Endothelial cell apoptosis is an early event in the development of inflammatory lung diseases such as acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD). In studies utilizing cultured human pulmonary endothelial cells we have shown that the Src family tyrosine kinase (STK) yes activated caspase‐3, while the STK fyn inhibited caspase‐3 activation. Therefore, in this study we tested the hypothesis that mice deficient in fyn will have more severe lipopolysaccharide (LPS)‐induced pulmonary apoptosis and lung injury than will similarly treated wild‐type mice. Wild‐type and fyn−/− mice (all on the same 129S1/SvImJ background) were given LPS 10 mg/kg intraperitoneally or saline for 24 hours and lungs were harvested for determination of proteins related to apoptosis. LPS treatment resulted in greater levels of cleaved caspase‐8, cleaved caspase‐9, cleaved caspase‐3, and p21 in the lungs from fyn−/− mice than in the lungs from wild‐type mice. In a second set of studies, lung sections from wild‐type and fyn−/− mice were stained for platelet endothelial cell adhesion molecule‐1 (PECAM‐1), we found that the fyn−/− mice had less PECAM‐1 expression, thicker alveolar septa, and more leukocyte infiltration than did wild‐type mice. In another set of studies wild‐type and fyn−/− mice were given LPS 2 mg/kg intratracheally or an equal volume of saline, and 24 hours later lung mechanics were measured using a Flexivent system (SCIREQ, Montreal, Canada). The fyn−/− mice had significantly (p<0.01) lower lung compliance (0.030 ± 0.003 ml/cmH2O) than did wild‐type mice (0.040 ± 0.001 ml/cmH2O). The fyn−/− mice also had significantly (p<0.05) higher tissue elastance (32.6 ± 3.1 cmH2O/mL) than did wild‐type mice (23.8 ± 0.8 cmH2O/mL). The fyn−/− mice had greater (p = 0.046) lung resistance (0.67±0.06 cmH2O/ml/s) than did wild‐type mice (0.55±0.02 cmH2O/ml/s). These results demonstrate that mice lacking fyn develop more apoptosis and more severe lung injury following LPS exposure than do wild‐type mice. These findings demonstrate that fyn is an important negative regulator of LPS‐induced apoptosis and the resultant lung injury in a mouse model of inflammatory lung diseases such as ARDS.

Src Family Tyrosine Kinase Signaling Regulates FilGAP through Association with RBM10.

FilGAP is a Rac-specific GTPase-activating protein (GAP) that suppresses lamellae formation. In this study, we have identified RBM10 (RNA Binding Motif domain protein 10) as a FilGAP-interacting protein. Although RBM10 is mostly localized in the nuclei in human melanoma A7 cells, forced expression of Src family tyrosine kinase Fyn induced translocation of RBM10 from nucleus into cell peripheries where RBM10 and FilGAP are co-localized. The translocation of RBM10 from nucleus appears to require catalytic activity of Fyn since kinase-negative Fyn mutant failed to induce translocation of RBM10 in A7 cells. When human breast carcinoma MDA-MB-231 cells are spreading on collagen-coated coverslips, endogenous FilGAP and RBM10 were localized at the cell periphery with tyrosine-phosphorylated proteins. RBM10 appears to be responsible for targeting FilGAP at the cell periphery because depletion of RBM10 by siRNA abrogated peripheral localization of FilGAP during cell spreading. Association of RBM10 with FilGAP may stimulate RacGAP activity of FilGAP. First, forced expression of RBM10 suppressed FilGAP-mediated cell spreading on collagen. Conversely, depletion of endogenous RBM10 by siRNA abolished FilGAP-mediated suppression of cell spreading on collagen. Second, FilGAP suppressed formation of membrane ruffles induced by Fyn and instead produced spiky cell protrusions at the cell periphery. This protrusive structure was also induced by depletion of Rac, suggesting that the formation of protrusions may be due to suppression of Rac by FilGAP. We found that depletion of RBM10 markedly reduced the formation of protrusions in cells transfected with Fyn and FilGAP. Finally, depletion of RBM10 blocked FilGAP-mediated suppression of ruffle formation induced by EGF. Taken together, these results suggest that Src family tyrosine kinase signaling may regulate FilGAP through association with RBM10.

Novel Tyrosine Phosphorylation Sites Fine Tune the Activity and Substrate Binding of Src Family Kinases

Src Family tyrosine Kinases (SFKs) are critical regulators of cellular processes including proliferation, migration and growth. SFKs are positively and negatively regulated by phosphorylation at two key tyrosine residues. We and others, over the course of hundreds of recent phosphoproteomic studies, have identified novel phosphotyrosines on SFKs from a variety of cells and tissues. These novel sites are located in important functional domains leading us to test the hypothesis that these sites can alter SFK enzymatic activity and binding. We used site-directed mutagenesis to generate point mutants in the SFK Fyn; phosphomimetic and non-phosphorylatable alleles exhibited altered kinase activity or affinity for a known binding partner, ESDN. Expression of SFKs in yeast followed by mass spectrometry analysis showed these sites can be the result of autophosphorylation. Finally, we generated transgeneic worms expressing various Fyn alleles in mechanosensory neurons and observed significantly altered neuronal migration patterns. We propose a model whereby SFK autophosphorylation at these novel tyrosine phosphorylation sites fine tunes SFK regulation of the wide array of cellular processes SFKs control. This project was supported by NSF grant IOS 1021795 and by the Vermont Genetics Network-grant 8P20GM103449 from the NIH INBRE Program of the NIGMS.

Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function.

Decreased nitric oxide (NO) bioavailability underlies a number of cardiovascular pathologies, including hypertension. The shear stress exerted by flowing blood is the main determinant of NO release. Rap1 promotes integrin- and cadherin-mediated signaling. Here, we show that Rap1 is a critical regulator of NO production and endothelial function. Rap1 deficiency in murine endothelium attenuates NO production and diminishes NO-dependent vasodilation, leading to endothelial dysfunction and hypertension, without deleterious effects on vessel integrity. Mechanistically, Rap1 is activated by shear stress, promotes the formation of the endothelial mechanosensing complex-comprised of PECAM-1, VE-cadherin and VEGFR2- and downstream signaling to NO production. Our study establishes a novel paradigm for Rap1 as a regulator of mechanotransduction.

Costimulatory Molecule DNAM-1 Is Essential for Optimal Differentiation of Memory Natural Killer Cells during Mouse Cytomegalovirus Infection

Recent studies demonstrate that natural killer (NK) cells have adaptive immune features. Here, we investigated the role of the costimulatory molecule DNAM-1 in the differentiation of NK cells in a mouse model of cytomegalovirus (MCMV) infection. Antibody blockade of DNAM-1 suppressed the expansion of MCMV-specific Ly49H(+) cells during viral infection and inhibited the generation of memory NK cells. Similarly, DNAM-1-deficient (Cd226(-/-)) Ly49H(+) NK cells exhibited intrinsic defects in expansion and differentiation into memory cells. Src-family tyrosine kinase Fyn and serine-threonine protein kinase C isoform eta (PKCη) signaling through DNAM-1 played distinct roles in the generation of MCMV-specific effector and memory NK cells. Thus, cooperative signaling through DNAM-1 and Ly49H are required for NK cell-mediated host defense against MCMV infection.

Genetic variation of FYN contributes to the molecular mechanisms of coping styles in healthy Chinese-Han participants

Genetic factors can influence specific human coping styles. Polymorphisms in the Src family tyrosine kinase FYN gene have been associated with several personality traits, but no studies have examined the possible relationship between FYN alleles and coping styles. To this end, we examined the association between three single nucleotide polymorphisms of FYN (rs706895, rs3730353, and rs6916861) and coping styles as measured by the Simplified Coping Style Questionnaire in 488 healthy Chinese-Han individuals. In the total sample population, there were no significant differences in the scores for active coping and passive coping among the genotypes of these three polymorphisms. In sex-specific analyses, however, both rs3730353 and rs6916861 polymorphisms showed a significant relationship with passive coping scores in female participants (rs3730353: χ(2)=8.08, P=0.018; rs6916861: χ(2)=7.78, P=0.020). Our results provided suggestive evidence that the FYN gene contributes toward the variance in human coping styles.

An anti-sulfatide antibody O4 immunoprecipitates sulfatide rafts including Fyn, Lyn and the G protein α subunit in rat primary immature oligodendrocytes

The association of sulfatide with specific proteins in oligodendrocytes was examined by co-immunoprecipitation with an anti-sulfatide antibody. Protein kinase activity was detected in precipitates with a monoclonal antibody to sulfatide (O4) from the rat primary immature oligodendrocytes. We conducted in vitro kinase assay of tyrosine phosphorylated proteins of 80, 59, 56, 53 and 40 kDa by gel electrophoresis. Of these proteins, the proteins of 59 kDa and 53/56 kDa were identified as the Src family tyrosine kinases Fyn and Lyn on the basis of their sequential immunoprecipitation with anti-Fyn and anti-Lyn antibodies, respectively. The 40 kDa protein was identified as the α subunit of the heterotrimeric G protein. These observations suggest that O4 immunoprecipitates sulfatide rafts including Fyn, Lyn and the α subunit of the heterotrimeric G protein.

Regulation of invariant natural killer T cell anti-tumor responses by the adaptor molecule Signaling Lymphocytic Activation Molecule-associated protein (SAP). (162.47)

Abstract Invariant natural killer T (iNKT) cells comprise a unique sub-lineage of innate-like T lymphocytes that participate in anti-tumor immune surveillance. However, several questions remain regarding the mechanisms by which these cells mediate killing of tumor cells. We observe that primary murine iNKT cell cytotoxicity against tumor cells is T cell receptor (TCR)-dependent and requires target cell presentation of iNKT cell-directed agonistic lipid antigens. Interestingly, expression of the cytoplasmic adaptor molecule SAP in primary murine iNKT cells is required for optimal TCR-mediated iNKT cell cytolytic responses towards B- and T-leukemia cells in vitro as well as iNKT cell-mediated control of leukemia cell growth in mice lacking CD8+ T and NK cells. iNKT cell cytotoxicity relies on expression of the Src family tyrosine kinase Fyn, a known SAP binding protein, and on the engagement of SLAM family receptors on iNKT and target cells. Of note, SAP- or Fyn- silenced human iNKT cells exhibit significantly impaired killing of T-leukemia cells in vitro, suggesting that SAP-associated signals are also critical for human iNKT cell anti-tumor cytotoxicity. These studies provide the first mechanistic insights into the signaling mechanisms underlying TCR-induced iNKT cell killing of tumor cells. Studies are ongoing to further elucidate the specific SLAM receptor(s) and downstream signaling mechanisms by which SAP regulates murine and human iNKT cell anti-tumor responses.

Regulation of NMDA receptors by the tyrosine kinase Fyn

The phosphorylation and trafficking of N-methyl-d-aspartate (NMDA) receptors are tightly regulated by the Src family tyrosine kinase Fyn, through dynamic interactions with various scaffolding proteins in the NMDA receptor complex. Fyn acts as a point of convergence for many signaling pathways that upregulate GluN2B-containing NMDA receptors. In the following review, we focus on Fyn signaling downstream of different G-protein-coupled receptors: the dopamine D1 receptor, and receptors cognate to the pituitary adenylate cyclase-activating polypeptide. The net result of activation of each of these signaling pathways is upregulation of GluN2B-containing NMDA receptors. The NMDA receptor is a major target of ethanol in the brain, and accumulating evidence suggests that Fyn mediates the effects of ethanol by regulating the phosphorylation of GluN2B NMDA receptor subunits. Furthermore, Fyn has been shown to regulate alcohol withdrawal and acute tolerance to ethanol through a GluN2B-dependent mechanism. In addition to its effects on NMDA receptor function, Fyn also modifies the threshold for synaptic plasticity at CA1 synapses, an effect that probably contributes to the effects of Fyn on spatial and contextual fear learning.

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders.

Phosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways

The transmembrane protein Tim-3 has been shown to negatively regulate T-cell-dependent immune responses and was recently demonstrated to be associated with the phenomenon of immune exhaustion, which can occur as a consequence of chronic viral infection. Unlike other negative regulators of T-cell function (e.g., PD-1), Tim-3 does not contain any obvious inhibitory signaling motifs. We have found that ectopic expression of Tim-3 in T cells leads to enhancement of T-cell receptor (TCR)-dependent signaling pathways, which was observed at the level of transcriptional reporters and endogenous cytokine production. We have exploited this observation to dissect what elements within the cytoplasmic tail of Tim-3 are required for coupling to downstream signaling pathways. Here we have demonstrated that two of the more membrane-proximal cytoplasmic tail tyrosines are required for Tim-3 signaling to T-cell activation pathways in a redundant fashion. Furthermore, we show that Tim-3 can directly bind to the Src family tyrosine kinase Fyn and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor. Thus, at least under conditions of short-term stimulation, Tim-3 can augment T-cell activation, although this effect can be blocked by the inclusion of an agonistic antibody to Tim-3. These findings should help further the study of Tim-3 function in other physiological settings, such as those that lead to immune exhaustion.

Role for the Src Family Kinase Fyn in Sphingolipid Acquisition by Chlamydiae

The bacterial obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound vacuole termed the inclusion. From within this protective environment, chlamydiae usurp numerous functions of the host cell to promote chlamydial survival and replication. Here we utilized a small interfering RNA (siRNA)-based screening protocol designed to identify host proteins involved in the trafficking of sphingomyelin to the chlamydial inclusion. Twenty-six host proteins whose deficiency significantly decreased sphingomyelin trafficking to the inclusion and 16 proteins whose deficiency significantly increased sphingomyelin trafficking to the inclusion were identified. The reduced sphingomyelin trafficking caused by downregulation of the Src family tyrosine kinase Fyn was confirmed in more-detailed analyses. Fyn silencing did not alter sphingomyelin synthesis or trafficking in the absence of chlamydial infection but reduced the amount of sphingomyelin trafficked to the inclusion in infected cells, as determined by two independent quantitative assays. Additionally, inhibition of Src family kinases resulted in increased cellular retention of sphingomyelin and significantly decreased incorporation into elementary bodies of both C. trachomatis and Chlamydophila caviae.

The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins

How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behavior1. Application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness2,3, also known as reinforcement4. While RhoA has been shown to play a role during reinforcement3, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signaling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signaling cascade that includes FAK and Ras.

LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte positive selection

The serine/threonine kinase LKB1 is a tumour suppressor that regulates cell growth, polarity, and proliferation in many different cell types. We previously demonstrated that LKB1 controls thymocyte survival via regulation of AMPK activation. In this study, we show that LKB1 was also involved in thymocyte positive selection through regulation of T cell receptor (TCR) signalling. Both Lck-Cre- and CD4-Cre-mediated deletion of LKB1 impaired the generation of mature CD4 and CD8 single positive (SP) thymocytes that might have resulted from the attenuated tyrosine phosphorylation of phospholipase C-γ 1 (PLCγ1) in the absence of LKB1. We found that LKB1 was directly phosphorylated by Lck at tyrosine residues 36, 261, and 365 and predominately interacted with LAT and PLCγ1 following TCR stimulation. Loss of LKB1 led to impaired recruitment of PLCγ1 to the LAT signalosome. Correlatively, LKB1-deficient thymocytes failed to upregulate lineage-specifying factors, and to differentiate into SP thymocytes even if their impaired survival was rescued. These observations indicated that LKB1 is a critical component involved in TCR signalling, and our studies provide novel insights into the mechanisms of LKB1-mediated thymocyte development.

Toll-interacting protein down-regulates src family tyrosine kinases fyn expression in human esophageal squamous cell carcinoma

Objective To determine the relationship between Src family tyrosine kinases Fyn ex- pression and Toll-interacting protein （Tollip） in human esophageal squamous cell carcinoma （ESCC）. Methods The Tollip expression was detected in 3 cases of ESCC and compared to the unremarkable epi- thelium by Western blotting. Tollip plasmid DNA （ 1 μg） was transfected into TEl cells and the Fyn/Tollip expression was examined by Western blotting. Results The Tollip expression level was lower in ESCC group than in UNR group. Tollip decreased Fyn protein expression in TEl cells. Conclusion ToUip may act as a negative regulator of Fyn in human ESCC, and play an important role in human ESCC progress. Key words: Esophageal/neoplasms ; Carcinoma, squamous cell; Fyn ; Tollip

Fyn Polymorphisms are Associated with Distinct Personality Traits in Healthy Chinese-Han Subjects

The Src family tyrosine kinase Fyn regulates a myriad of neurophysiological processes, including learning and memory. To date, the role of Fyn in the neurological mechanisms that determine personality traits has not been addressed. To this end, we determined the association between the rs706895C/T polymorphism of the Fyn gene (FYN) and personality traits measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. There were no significant differences in the total scores for novelty seeking (χ² = 5.12, P = 0.077), harm avoidance (HA; χ² = 2.63, P = 0.269), or reward dependence (RD; χ² = 3.94, P = 0.139) among the rs706895C/T genotypes. In sub-item analyses, however, both fear of uncertainty (HA2; χ² = 7.84, P = 0.020) and sentimentality (RD1; χ² = 8.27; P = 0.016) scores were significantly different among rs706895C/T genotypes. Our results suggest that FYN alleles can contribute to the variance in human personality traits.