YANK2 activated by Fyn promotes glioma tumorigenesis via the mTOR-independent p70S6K activation pathway.

Glioma, particularly glioblastomas (GBM), is incurable brain tumor. The most targeted receptor tyrosine kinase (RTKs) drugs did not bring benefit to GBM patients. The mechanism of glioma growth continues to be explored to find more effective treatment. Here, we reported that Ser/Thr protein kinase YANK2 (yet another kinase 2) is upregulated in glioma tissues and promotes the growth and proliferation of glioma in vitro and in vivo. Further, we confirmed that oncogene Fyn directly activated YANK2 through phosphorylation its Y110, and Fyn-mediated YANK2 phosphorylation at Y110 site promotes glioma growth by increasing its stability. Finally, YANK2 was proved to be a novel upstream kinase of p70S6K and promotes glioma growth by directly phosphorylating p70S6K at T389. Taken together, we found a new mTOR-independent p70S6K activation pathway, Fyn-YANK2-p70S6K, which promotes glioma growth, and YANK2 is a potential oncogene and serves as a novel therapeutic target for glioma.

Deficiency of Nuclear Receptor Coactivator 3 Aggravates Diabetic Kidney Disease by Impairing Podocyte Autophagy.

Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR-γ dependent way. Podocyte-specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

Fyn, Blk, and Lyn kinase inhibitors: A mini-review on medicinal attributes, research progress, and future insights.

Fyn, Blk, and Lyn are part of a group of proteins called Src family kinases. They are crucial in controlling cell communication and their response to the growth, changes, and immune system. Blocking these proteins with inhibitors can be a way to treat diseases where these proteins are too active. The primary mode of action of these inhibitors is to inhibit the phosphorylation of Fyn, Blk, and Lyn receptors, which in turn affects how signals pass within the cells. This review shows the structural and functional aspects of Fyn, Blk, and Lyn kinases, highlighting the significance of their dysregulation in diseases such as cancer and autoimmune disorders. The discussion encompasses the design strategies, SAR analysis, and chemical characteristics of effective inhibitors, shedding light on their specificity and potency. Furthermore, it explores the progress of clinical trials of these inhibitors, emphasizing their potential therapeutic applications.

Constraint-Induced Movement Therapy Promotes Myelin Remodeling and Motor Function by Mediating Sox2/Fyn Signals in Rats With Hemiplegic Cerebral Palsy.

OBJECTIVE: Hypoxic-ischemic brain injury in infants often leads to hemiplegic motor dysfunction. The mechanism of their motor dysfunction has been attributed to deficiencies of the transcription factor sex-determining region (SRY) box 2 (Sox2) or the non-receptor-type tyrosine kinase Fyn (involved in neuronal signal transduction), which causes a defect in myelin formation. Constraint-induced movement therapy (CIMT) following cerebral hypoxia-ischemia may stimulate myelin growth by regulating Sox2/Fyn, Ras homolog protein family A (RhoA), and rho-associated kinase 2 (ROCK2) expression levels. This study investigated how Sox2/Fyn regulates myelin remodeling following CIMT to improve motor function in rats with hemiplegic cerebral palsy (HCP). METHODS: To investigate the mechanism of Sox2 involvement in myelin growth and neural function in rats with HCP, Lentivirus (Lenti)-Sox2 adeno-associated virus and negative control-Lenti-Sox2 (LS) adeno-associated virus were injected into the lateral ventricle. The rats were divided into a control group and an HCP group with different interventions (CIMT, LS, or negative control-LS [NS] treatment), yielding the HCP, HCP plus CIMT (HCP + CIMT), HCP + LS, HCP + LS + CIMT, HCP + NS, and HCP + NS + CIMT groups. Front-limb suspension and RotaRod tests, Golgi-Cox staining, transmission electron microscopy, immunofluorescence staining, western blotting, and quantitative polymerase chain reaction experiments were used to analyze the motor function, dendrite/axon area, myelin ultrastructure, and levels of expression of oligodendrocytes and Sox2/Fyn/RhoA/ROCK2 in the motor cortex. RESULTS: The rats in the HCP + LS + CIMT group had better values for motor function, dendrite/axon area, myelin ultrastructure, oligodendrocytes, and Sox2/Fyn/RhoA/ROCK2 expression in the motor cortex than rats in the HCP and HCP + NS groups. The improvement of motor function and myelin remodeling, the expression of oligodendrocytes, and the expression of Sox2/Fyn/RhoA/ROCK2 in the HCP + LS group were similar to those in the HCP + CIMT group. CONCLUSION: CIMT might overcome RhoA/ROCK2 signaling by upregulating the transcription of Sox2 to Fyn in the brain to induce the maturation and differentiation of oligodendrocytes, thereby promoting myelin remodeling and improving motor function in rats with HCP. IMPACT: The pathway mediated by Sox2/Fyn could be a promising therapeutic target for HCP.

Tau-S214 Phosphorylation Inhibits Fyn Kinase Interaction and Increases the Decay Time of NMDAR-mediated Current.

Fyn kinase SH3 domain interaction with PXXP motif in the Tau protein is implicated in AD pathology and is central to NMDAR function. Among seven PXXP motifs localized in proline-rich domain of Tau protein, tandem 5th and 6th PXXP motifs are critical to Fyn-SH3 domain interaction. Here, we report the crystal structure of Fyn-SH3 -Tau (207-221) peptide consisting of 5th and 6th PXXP motif complex to 1.01 Å resolution. Among five AD-specific phosphorylation sites encompassing the 5th and 6th PXXP motifs, only S214 residue showed interaction with SH3 domain. Biophysical studies showed that Tau (207-221) with S214-phosphorylation (pS214) inhibits its interaction with Fyn-SH3 domain. The individual administration of Tau (207-221) with/without pS214 peptides to a single neuron increased the decay time of evoked NMDA current response. Recordings of spontaneous NMDA EPSCs at +40 mV indicate an increase in frequency and amplitude of events for the Tau (207-221) peptide. Conversely, the Tau (207-221) with pS214 peptide exhibited a noteworthy amplitude increase alongside a prolonged decay time. These outcomes underscore the distinctive modalities of action associated with each peptide in the study. Overall, this study provides insights into how Tau (207-221) with/without pS214 affects the molecular framework of NMDAR signaling, indicating its involvement in Tau-related pathogenesis.

Unveiling Phytoconstituents with Inhibitory Potential Against Tyrosine-Protein Kinase Fyn: A Comprehensive Virtual Screening Approach Targeting Alzheimer's Disease.

BACKGROUND: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. OBJECTIVE: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. METHODS: Through a comprehensive approach involving molecular docking, drug likeliness filters, and molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. RESULTS: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. CONCLUSION: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies.

Advances in the expression and function of Fyn in different human tumors

The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell metabolism. Recently, Fyn has been found to be expressed in various tumor tissues, and the expression and function of Fyn vary between tumors, with Fyn acting as an oncogene to promote proliferation and metastasis in some tumors. This article summarizes the recent studies on the role of Fyn in different human tumors, focusing on the role of Fyn in melanoma, breast cancer, glioma, lung cancer, and peripheral T-cell lymphoma in order to provide a basis for future research and targeted therapy in different human tumors.(AU)

Insights into the role of PHLPP2/Akt/GSK3ß/Fyn kinase/Nrf2 trajectory in the reno-protective effect of rosuvastatin against colistin-induced acute kidney injury in rats.

OBJECTIVES: Oxidative stress-mediated colistin's nephrotoxicity is associated with the diminished activity of nuclear factor erythroid 2-related factor 2 (Nrf2) that is primarily correlated with cellular PH domain and leucine-rich repeat protein phosphatase (PHLPP2) levels. This study investigated the possible modulation of PHLPP2/protein kinase B (Akt) trajectory as a critical regulator of Nrf2 stability by rosuvastatin (RST) to guard against colistin-induced oxidative renal damage in rats. METHODS: Colistin (300,000 IU/kg/day; i.p.) was injected for 6 consecutive days, and rats were treated simultaneously with RST orally at 10 or 20 mg/kg. KEY FINDINGS: RST enhanced renal nuclear Nrf2 translocation as revealed by immunohistochemical staining to boost the renal antioxidants, superoxide dismutase (SOD) and reduced glutathione (GSH) along with a marked reduction in caspase-3. Accordingly, rats treated with RST showed significant restoration of normal renal function and histological features. On the molecular level, RST effectively decreased the mRNA expression of PHLPP2 to promote Akt phosphorylation. Consequently, it deactivated GSK-3ß and reduced the gene expression of Fyn kinase in renal tissues. CONCLUSIONS: RST could attenuate colistin-induced oxidative acute kidney injury via its suppressive effect on PHLPP2 to endorse Nrf2 activity through modulating Akt/GSK3 ß/Fyn kinase trajectory.

Advances in the expression and function of Fyn in different human tumors.

The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell metabolism. Recently, Fyn has been found to be expressed in various tumor tissues, and the expression and function of Fyn vary between tumors, with Fyn acting as an oncogene to promote proliferation and metastasis in some tumors. This article summarizes the recent studies on the role of Fyn in different human tumors, focusing on the role of Fyn in melanoma, breast cancer, glioma, lung cancer, and peripheral T-cell lymphoma in order to provide a basis for future research and targeted therapy in different human tumors.

Podocarpusflavone alleviated renal fibrosis in obstructive nephropathy by inhibiting Fyn/Stat3 signaling pathway.

Tubulointerstitial fibrosis is a common pathological change in end-stage renal disease. However, limited treatment methods are developed, and unexplained potential mechanisms of renal diseases are urgent problems to be solved. In the present research, we first elucidated the role of podocarpusflavone (POD), a biflavone compound, in unilateral ureteral obstruction (UUO) in rodent model which is characterized by inflammation and fibrosis. The changes in histology and immunohistochemistry were observed that POD exerted renoprotective effects by retarding the infiltration of macrophage and aberrant deposition of ɑ-SMA, Col1a1, and fibronectin. Consistent with in vivo assay, POD treatment also ameliorated the process of fibrosis in TGF-ß1-stimulated renal tubular epithelial cells and inflammation in LPS-induced RAW264.7 cells in vitro. In terms of mechanism, our results showed that treatment with POD inhibited the aggravated activation of Fyn in the UUO group, and weakened the level of phosphorylation of Stat3 which indicated that POD may alleviate the process of fibrosis by the Fyn/Stat3 signaling pathway. Furthermore, the gain of function assay by lentivirus-mediated exogenous forced expression of Fyn abrogated the therapeutic effect of the POD on renal fibrosis and inflammation. Collectively, it can be concluded that POD exerted a protective effect on renal fibrosis by mediating Fyn/Stat3 signaling pathway.

FYN: emerging biological roles and potential therapeutic targets in cancer.

Src family protein kinases (SFKs) play a key role in cell adhesion, invasion, proliferation, survival, apoptosis, and angiogenesis during tumor development. In humans, SFKs consists of eight family members with similar structure and function. There is a high level of overexpression or hyperactivity of SFKs in tumor, and they play an important role in multiple signaling pathways involved in tumorigenesis. FYN is a member of the SFKs that regulate normal cellular processes. Additionally, FYN is highly expressed in many cancers and promotes cancer growth and metastasis through diverse biological functions such as cell growth, apoptosis, and motility migration, as well as the development of drug resistance in many tumors. Moreover, FYN is involved in the regulation of multiple cancer-related signaling pathways, including interactions with ERK, COX-2, STAT5, MET and AKT. FYN is therefore an attractive therapeutic target for various tumor types, and suppressing FYN can improve the prognosis and prolong the life of patients. The purpose of this review is to provide an overview of FYN's structure, expression, upstream regulators, downstream substrate molecules, and biological functions in tumors.

Src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma.

Although Src is one of the oldest and most investigated oncoproteins, its function in tumor malignancy remains to be defined further. In this study, we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma (ESCC) both in vitro and in vivo, whereas it did not produce growth-inhibitory effects on normal esophageal epithelial cells (NEECs). Importantly, we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases (SFKs), such as Fyn or Lyn, to form heterodimers. Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2 (Fyn Tyr185 or Lyn Tyr183) and kinase domains (Fyn Tyr420 or Lyn Tyr397), which critically contributed to ESCC development. By contrast, Src could not form heterodimers with Fyn or Lyn in NEECs. We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways, such as JAK/STAT, mTOR, stemness-related, and metabolism-related pathways. Results of the real-time polymerase chain reaction (RT-PCR) assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules. Furthermore, results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr419, Fyn Tyr185 or Tyr420, and Lyn Tyr183 or Tyr397 could be biomarkers of ESCC prognosis. This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.

Role of Fyn in hematological malignancies.

BACKGROUND: Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and Fyn-C. Fyn-T is highly expressed in T lymphocytes, and its expression level is significantly higher in mature T cells than in immature T cells. The abnormal expression of Fyn is closely related to the metabolism, proliferation, and migration of tumor cells. Recent studies have shown that Fyn is expressed in a variety of tumor tissues, and its expression and function vary among different tumors. In some tumors, Fyn acts as a pro-oncogene to promote tumor proliferation and metastasis. Moreover, Fyn mutations have been detected in many hematological tumors in recent years, suggesting a critical regulatory role of Fyn in the development of malignancies. METHODS: This review analyzed the relevant literature in PubMed and other databases. PURPOSE: The aim of this study was to systemically review recent research findings on various aspects of Fyn in the pathogenesis and treatment of different types of hematological malignancies and suggests possible future research directions for targeted tumor therapy. CONCLUSION: Fyn could be a novel prognostic marker and therapeutic target. Treatment option targeting Fyn might be beneficial for future studies.

CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance.

Signal transduction induced by chimeric antigen receptors (CARs) is generally believed to rely on the activity of the SRC family kinase (SFK) LCK, as is the case with T cell receptor (TCR) signaling. Here, we show that CAR signaling occurs in the absence of LCK. This LCK-independent signaling requires the related SFK FYN and a CD28 intracellular domain within the CAR. LCK-deficient CAR-T cells are strongly signaled through CAR and have better in vivo efficacy with reduced exhaustion phenotype and enhanced induction of memory and proliferation. These distinctions can be attributed to the fact that FYN signaling tends to promote proliferation and survival, whereas LCK signaling promotes strong signaling that tends to lead to exhaustion. This non-canonical signaling of CAR-T cells provides insight into the initiation of both TCR and CAR signaling and has important clinical implications for improvement of CAR function.

Phosphorylation of mammalian mitochondrial EF-Tu by Fyn and c-Src kinases.

Src Family Kinases (SFKs) are tyrosine kinases known to regulate glucose and fatty acid metabolism as well as oxidative phosphorylation (OXPHOS) in mammalian mitochondria. We and others discovered the association of the SFK kinases Fyn and c-Src with mitochondrial translation components. This translational system is responsible for the synthesis of 13 mitochondrial (mt)-encoded subunits of the OXPHOS complexes and is, thus, essential for energy generation. Mitochondrial ribosomal proteins and various translation elongation factors including Tu (EF-Tumt) have been identified as possible Fyn and c-Src kinase targets. However, the phosphorylation of specific residues in EF-Tumt by these kinases and their roles in the regulation of protein synthesis are yet to be explored. In this study, we report the association of EF-Tumt with cSrc kinase and mapping of phosphorylated Tyr (pTyr) residues by these kinases. We determined that a specific Tyr residue in EF-Tumt at position 266 (EF-Tumt-Y266), located in a highly conserved c-Src consensus motif is one of the major phosphorylation sites. The potential role of EF-Tumt-Y266 phosphorylation in regulation of mitochondrial translation investigated by site-directed mutagenesis. Its phosphomimetic to Glu residue (EF-Tumt-E266) inhibited ternary complex (EF-Tumt•GTP•aatRNA) formation and translation in vitro. Our findings along with data mining analysis of the c-Src knock out (KO) mice proteome suggest that the SFKs have possible roles for regulation of mitochondrial protein synthesis and oxidative energy metabolism in animals.

Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates.

Fyn is a Src kinase that controls critical signalling cascades and has been implicated in learning and memory. Postsynaptic enrichment of Fyn underpins synaptotoxicity in dementias such as Alzheimer's disease and frontotemporal lobar degeneration with Tau pathology (FTLD-Tau). The FLTD P301L mutant Tau is associated with a higher propensity to undergo liquid-liquid phase separation (LLPS) and form biomolecular condensates. Expression of P301L mutant Tau promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites by an unknown mechanism. Here, we used single-particle tracking photoactivated localisation microscopy to demonstrate that the opening of Fyn into its primed conformation promotes its nanoclustering in dendrites leading to increased Fyn/ERK/S6 downstream signalling. Preventing the auto-inhibitory closed conformation of Fyn through phospho-inhibition or through perturbation of its SH3 domain increased Fyn's nanoscale trapping, whereas inhibition of the catalytic domain had no impact. By combining pharmacological and genetic approaches, we demonstrate that P301L Tau enhanced both Fyn nanoclustering and Fyn/ERK/S6 signalling via its ability to form biomolecular condensates. Together, our findings demonstrate that Fyn alternates between a closed and an open conformation, the latter being enzymatically active and clustered. Furthermore, pathogenic immobilisation of Fyn relies on the ability of P301L Tau to form biomolecular condensates, thus highlighting the critical importance of LLPS in controlling nanoclustering and downstream intracellular signalling events.

Restored Fyn Levels in Huntington's Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity.

N-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington's disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD.

Fyn and Lyn gene polymorphisms impact the risk of thyroid cancer.

Thyroid cancer is the most common malignancy of the endocrine glands, and during last couple of decades, its incidence has risen alarmingly, across the globe. Etiology of thyroid cancer is still debatable. There are a few worth mentioning risk factors which contribute to initiation of abnormalities in thyroid gland leading to cancer. Genetic instability is major risk factors in thyroid carcinogenesis. Among the genetic factors, the Src family of genes (Src, Yes1, Fyn and Lyn) have been implicated in many cancers but there is little data regarding the association of these (Src, Yes1, Fyn and Lyn) genes with thyroid carcinogenesis. Fyn and Lyn genes of Src family found engaged in proliferation, migration, invasion, angiogenesis, and metastasis in different cancers. This study was planned to examine the effect of Fyn and Lyn SNPs on thyroid cancer risk in Pakistani population in 500 patients and 500 controls. Three polymorphisms of Fyn gene (rs6916861, rs2182644 and rs12910) and three polymorphisms of Lyn gene (rs2668011, rs45587541 and rs45489500) were analyzed using Tetra-primer ARMS-PCR followed by DNA sequencing. SNP rs6916861 of Fyn gene mutant genotype (CC) showed statistically significant threefold increased risk of thyroid cancer (P < 0.0001). In case of rs2182644 of Fyn gene, mutant genotype (AA) indicated statistically significant 17-fold increased risk of thyroid cancer (P < 0.0001). Statistically significant threefold increased risk of thyroid cancer was observed in genotype AC (P < 0.0001) of Fyn gene polymorphism rs12910. In SNP rs2668011 of Lyn gene, TT genotype showed statistically significant threefold increased risk of thyroid cancer (P < 0.0001). In case of rs45587541 of Lyn gene, GA genotypes showed statistically significant 11-fold increased risk in thyroid cancer (P < 0.0001). Haplotype analysis revealed that AAATAG*, AGACAG*, AGCCAA*, AGCCAG*, CAATAG*, CGCCAG* and CGCCGA* haplotypes of Fyn and Lyn polymorphisms are associated with increased thyroid cancer risk. These results showed that genotypes and allele distribution of Fyn and Lyn are significantly linked with increased thyroid cancer risk and could be genetic adjuster for said disease.

Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress.

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD.

FYN regulates cell adhesion at the blood-testis barrier and the apical ectoplasmic specialization via its effect on Arp3 in the mouse testis.

FYN is a non-receptor tyrosine kinase of the SRC family that facilitates virus entry across epithelial tight junctions. However, the role of FYN in mammalian testes in maintaining the blood-testis barrier (BTB) integrity and the adhesion of germ cells to Sertoli cells are not well defined. Here, we show that FYN is a component of the BTB and the apical ectoplasmic specialization (ES) at Sertoli-Sertoli and Sertoli-spermatid interfaces, respectively, and is expressed extensively in mouse testes during postnatal development. FYN was shown to be structurally linked to the actin and microtubule-based cytoskeletons. An in vivo model was used to explore the modulatory effect of FYN on BTB and apical ES dynamics within the testes when adult mice were treated intraperitoneally with CdCl2 (3 mg/kg body weight). The CdCl2-induced epithelial restructuring was associated with a transient increase in the interaction between FYN and the actin branching/nucleation protein Arp3, as well as an induction of Arp3 phosphorylation, which possibly lead to actin cytoskeleton remodeling, resulting in BTB damage and germ cell loss in the seminiferous epithelium. Based on the results, we propose a model in which FYN and Arp3 form a protein complex that is responsible for junction reorganization events at the apical ES and the BTB. It is also possible for viruses to break through the BTB and enter the immunoprivileged testicular microenvironment via this mechanism.