p(HGNC:FYN)

Entity

Name

FYN

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

JAK-2, also implicated in the neuroprotective pathway, may play a role in linking nAChR action with calcium signaling, because JAK-2 phosphorylates inositol 1,4,5-triphosphate receptors through its activation of FYN (Wallace et al., 2005). PubMed:19293145

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

In a microarray study comparing brains from patients with AD with control brains, FYN was found to be significantly upregulated in AD (Wang et al., 2003a). In this context, it is of interest that FYN has also been shown to activate the PI3K/AKT cascade, thereby inhibiting apoptosis (Tang et al., 2007). Indeed, FYN is required for phos- phorylation of phosphoinositide 3-kinase enhancer (PIKE), which itself regulates AKT (Fig. 3). PIKE binds to AKT and up-regulates its kinase a ctivity, thereby reducing apoptosis. Phosphorylation protects PIKE from caspase cleavage, hence FYN is antiapoptotic (Tang et al., 2007). PubMed:19293145

Abetao exposure induced a translocation of tau into the PSD fraction (***p  0.0002, 2-tailed Student’s t test; control 20.12  1228 vs Abetao 29.74  1.748, N  12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10  2.557 vs Abetao 33.3  2153, N  9 independent culture), GluA1 (**p  0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p  0.0041, 2-tailed Student’s t test; control 19.42  1.337 vs Abetao 29.67  2.181, N  6 independent cultures; Fig. 6D). PubMed:24760868

We analyzed actin and tau in the PSD-enriched fraction from primary cortical neurons treated with jasplakinolide (Fig. 5E). We observed that increased neuronal F-actin content promotes concurrent tau enrichment (*p0.0150, 2-tailed Student’s t test; control 17.49  0.7755 vs jasplakinolide 27.02  2719, N  4 independent cultures; Fig. 5F). GLUA1, the membrane trafficking of which is known to be actin dependent, was increased (*p 0.0279, 2-tailed Student’s t test; control 16.91  1015 vs jasplakinolide 31.00  4.778, N  4 independent cultures). The amount of Fyn in the PSD was decreased (*p  0.0265, 2-tailed Student’s t test; control 27.25 5.003 vs jasplakinolide 11.71  1.786, N  4 independent cultures). PubMed:24760868

Therefore, during a long-lasting synaptic activation, we observed an increase in tau, fyn, actin, GluA1, and PSD-95 content in the PSD-positive fraction, which is consistent with the characteristic features of synaptic plasticity (Ehlers, 2003). PubMed:24760868

In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR). PubMed:26751493

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR). PubMed:26751493

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

In a microarray study comparing brains from patients with AD with control brains, FYN was found to be significantly upregulated in AD (Wang et al., 2003a). In this context, it is of interest that FYN has also been shown to activate the PI3K/AKT cascade, thereby inhibiting apoptosis (Tang et al., 2007). Indeed, FYN is required for phos- phorylation of phosphoinositide 3-kinase enhancer (PIKE), which itself regulates AKT (Fig. 3). PIKE binds to AKT and up-regulates its kinase a ctivity, thereby reducing apoptosis. Phosphorylation protects PIKE from caspase cleavage, hence FYN is antiapoptotic (Tang et al., 2007). PubMed:19293145

In a microarray study comparing brains from patients with AD with control brains, FYN was found to be significantly upregulated in AD (Wang et al., 2003a). In this context, it is of interest that FYN has also been shown to activate the PI3K/AKT cascade, thereby inhibiting apoptosis (Tang et al., 2007). Indeed, FYN is required for phos- phorylation of phosphoinositide 3-kinase enhancer (PIKE), which itself regulates AKT (Fig. 3). PIKE binds to AKT and up-regulates its kinase a ctivity, thereby reducing apoptosis. Phosphorylation protects PIKE from caspase cleavage, hence FYN is antiapoptotic (Tang et al., 2007). PubMed:19293145

In a microarray study comparing brains from patients with AD with control brains, FYN was found to be significantly upregulated in AD (Wang et al., 2003a). In this context, it is of interest that FYN has also been shown to activate the PI3K/AKT cascade, thereby inhibiting apoptosis (Tang et al., 2007). Indeed, FYN is required for phos- phorylation of phosphoinositide 3-kinase enhancer (PIKE), which itself regulates AKT (Fig. 3). PIKE binds to AKT and up-regulates its kinase a ctivity, thereby reducing apoptosis. Phosphorylation protects PIKE from caspase cleavage, hence FYN is antiapoptotic (Tang et al., 2007). PubMed:19293145

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

Furthermore, inhibitors of SRC, a closely related tyrosine kinase, also prevent nicotinic protection of differentiated PC12 cells against serum-deprivation-induced cell death (Li et al., 1999b), and inhibitors of FYN or Janus kinase-2 (JAK-2) block the neuroprotection against Abeta toxicity of therapeutic AChE inhibitors (Takada-Takatori et al., 2006). PubMed:19293145

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

FYN physically interacts with and phosphorylates tau protein, and the affinity of this physical interaction is enhanced in AD-associated mutations in tau protein (Bhaskar et al., 2005). Abeta rapidly induces tyrosine phosphorylation of many proteins (including tau protein) in human and cultured rat cortical neurons (Williamson et al., 2002). This phosphorylation is concomitant with phosphorylation and inactivation of focal adhesion kinase 1 (FADK1, a major downstream target of FYN), is blocked by inhibitors of SRC kinases and PI3K, and involves FYN associating physically with FADK1 (Williamson et al., 2002). PubMed:19293145

It has been shown that the alpha7 receptors, but not the alpha3beta2 receptors, specifically trigger calcium release from intracellular stores by activating ryanodine receptors. Such a specific functional coupling of alpha7 receptors and ryanodine-sensitive stores may provide another site of therapeutic intervention. However, the sustained calcium rise seen in these cells upon prolonged nicotine administration, which is more likely to be of relevance to neuroprotection than short-term responses, is more dependent upon the activation of inositol 1,4,5-triphosphate receptors (Dajas-Bailador et al., 2002a), which are also a target for phosphorylation by FYN (Cui et al., 2004). PubMed:19293145

JAK-2, also implicated in the neuroprotective pathway, may play a role in linking nAChR action with calcium signaling, because JAK-2 phosphorylates inositol 1,4,5-triphosphate receptors through its activation of FYN (Wallace et al., 2005). PubMed:19293145

Therefore, during a long-lasting synaptic activation, we observed an increase in tau, fyn, actin, GluA1, and PSD-95 content in the PSD-positive fraction, which is consistent with the characteristic features of synaptic plasticity (Ehlers, 2003). PubMed:24760868

In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR). PubMed:26751493

Tyrosine kinases target Y18 [fyn, (79)] and Y394 [abl, (31)]. PubMed:17493042

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

Furthermore, Tau binds Fyn both in neuronal and oligodendroglial cells (Brandt et al. 1995; Klein et al.2002), and Fyn phosphorylates Tau in neuronal cells (Lee et al. 2004). The main Fyn SH3 domain-binding PXXP motif (Pro, Lys, Ser, Pro) in adult rat Tau is at the residues 223-226 (Kosik et al. 1989; Lee et al. 1998). PubMed:18680553

Here we demonstrate that the Tau-Fyn interaction has a role in developmental myelination. CG-4 cells were stably transfected with control and experimental truncated Tau and transplanted in the brain and spinal cord of the md rats. In the brain, experimental cells have a severe defect in their ability to extend cellular processes and form myelin; in the spinal cord the cells extend cellular processes but the extent of myelination rostral and caudal to the injection site was decreased compared to control. Cultured experimental cells display shorter cellular process length. In addition experimental cells have Fyn largely in the cell body, whereas control cells distribute Fyn both in the cell body and the processes. Taken together these results demonstrate a direct effect of Tau in OLGs in in vivo myelination. PubMed:18680553

In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR). PubMed:26751493

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

In addition, tau can be phosphorylated by tyrosine kinases such as the SRC family members LCK, SYK and FYN at Tyr18, and the ABL family members ARG and ABL1 at Tyr394 (REF. 45). PubMed:26631930

In addition, dendritic tau could serve as a protein scaffold to deliver the kinase FYN to postsynaptic sites, where FYN phosphorylates subunit 2 of the NMDA receptor (NR2B; also known as GluN2B), resulting in the stabilization of the interaction of this receptor interaction with postsynaptic density protein 95 (PSD95; also known as DLG4), potentiating glutamatergic signalling and thereby enhancing Aβ toxicity. PubMed:26631930