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Event: 1884

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Inhibition of Fyna

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Inhibition of Fyna
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
protein tyrosine kinase activity tyrosine-protein kinase fyna (zebrafish) decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Inhibition of Fyna leading to increased mortality MolecularInitiatingEvent Brendan Ferreri-Hanberry (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
zebrafish Danio rerio High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Larvae High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Src family kinases (SFKs) include nine members (i.e., Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn) and regulate multiple signal transduction pathways involved in growth, proliferation, differentiation, migration, metabolism and apoptosis, interacting with a diverse array of molecules, including growth factor receptors, cell–cell adhesion receptors, integrins and steroid hormone receptors (Schenone et al., 2007). Protein kinases enable transfer of γ phosphate of ATP to specific amino acids of protein substrates (tyrosine, serine, threonine, or even histidine residues) (Saito, 2001). There are two major groups of tyrosine kinases: receptor and nonreceptor tyrosine kinases. Nonreceptor tyrosine kinases (cytoplasmatic proteins) are important components of signaling pathways through different receptors such as receptor tyrosine kinases, G-protein coupled receptors, or T-cell receptors (TCR) on the cell surface (Hanrs & Hunter, 1995).

Fyna (Src family tyrosine kinase A) is a nonreceptor tyrosine kinase.  It is involved in several processes, including adherens junction maintenance and gastrulation. Fyna localizes to the cytosol and the nucleus. It is expressed in the central nervous system, olfactory placode, peripheral olfactory organ, and retina. Human ortholog(s) of this gene are implicated in Alzheimer's disease and schizophrenia. Zebrafish Fyna gene is orthologous to human FYN (FYN proto-oncogene, Src family tyrosine kinase) (ZFIN Gene: Fyna, n.d.) and shares 89% sequence identity (full length sequence and kinase domain) with the human FYN gene (Challa & Chatti, 2013).

The Src family kinases are of a modular nature, consisting of a unique N-terminal sequence, three protein modules including the SH3, SH2, and kinase domains, and a C-terminal tail. The modules play an important role in enzyme reactions (Lamers et al., 2003). Fyna kinase activity, like that of other Src family kinases, is regulated by intramolecular interactions that depend on equilibrium between tyrosine phosphorylation and dephosphorylation. In the basal state, catalytic activity is constrained by engagement of the SH2 domain by a phosphorylated C-terminal tyrosine 531 (Krämer-Albers & White, 2011), after activation enzymes transmit signals from several surface receptors to target proteins by phosphorylating tyrosine residues (Sen and Johnson, 2011). Crystal structures of the SH2 and SH3 domains of the Fyna kinase reveal its binding specificity for peptide inhibitors (Morton et al., 1996; Mulhern et al., 1997). Binding of inhibitors to fyna domains inhibits its activity. Research in inhibition of Fyna kinase is mostly due its role in Alzheimer's disease (AD) and anti-inflamatory therapy (Löwenberg et al., 2005).

There are multiple known Fyna kinase inhibitors (see Evidence for perturbation by stressor).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Changes in activity of Fyna kinase can be evaluated with enzyme-linked immunosorbent assay (ELISA). This type of ELISA method is based on kinase phosphorylation of an immobilized substrate, which is detected using anti-tyrosine phosphate antibody. The extent of the substrate phosphorylation can be measured by absorbance, fluorescence, or fluorescence polarization (Jelić et al., 2007).

Adp-GloTM Kinase Assay can be used to measure Fyna kinase activity. The assay is well suited for measuring the effects chemical compounds have on the activity of a broad range of purified kinases, making it ideal for both primary screening as well as kinase selectivity profiling (Zegzouti et al., 2009).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Theoretically, this MIE is applicable to any organisms with the Fyna kinase (zebrafish and other vertebrate models). While, in zebrafish Fyna inhibition was achieved with kinase dead (KD) point mutant of Fyna (St. Clair et al., 2018), chemical inhibition most pertaining to this AOP was mostly studied in human (Green et al., 2009; Jelić et al., 2007; Kinoshita et al., 2006; Lamers et al., 2003; Toullec et al., 1991) and mouse (Morisot et al., 2019; Nygaard et al., 2014) cell lines. 

References

List of the literature that was cited for this KE description. More help

Challa, A. K., & Chatti, K. (2013). Conservation and Early Expression of Zebrafish Tyrosine Kinases Support the Utility of Zebrafish as a Model for Tyrosine Kinase Biology. 10(3). https://doi.org/10.1089/zeb.2012.0781

Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., Elvin, P., Boyer, B., Carragher, N., Plé, P. A., Bermingham, A., Holdgate, G. A., Ward, W. H. J., Hennequin, L. F., Davies, B. R., & Costello, G. F. (2009). Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Molecular Oncology, 3(3), 248–261. https://doi.org/10.1016/j.molonc.2009.01.002

Hanrs, S. K., & Hunter, T. (1995). The eukaryotic protein kinase superfamily: idnase. (catalytic) domam structure and classification. https://doi.org/10.1096/fasebj.9.8.7768349

Jelić, D., Mildner, B., Koštrun, S., Nujić, K., Verbanac, D., Čulić, O., Antolović, R., & Brandt, W. (2007). Homology modeling of human Fyn kinase structure: Discovery of rosmarinic acid as a new Fyn kinase inhibitor and in Silico study of its possible binding modes. Journal of Medicinal Chemistry, 50(6), 1090–1100. https://doi.org/10.1021/jm0607202

Kinoshita, T., Matsubara, M., Ishiguro, H., Okita, K., & Tada, T. (2006). Structure of human Fyn kinase domain complexed with staurosporine. Biochemical and Biophysical Research Communications, 346(3), 840–844. https://doi.org/10.1016/j.bbrc.2006.05.212

Krämer-Albers, E.-M., & White, R. (2011). From axon-glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase. Cell. Mol. Life Sci. https://doi.org/10.1007/s00018-010-0616-z

Lamers, M. B. A. C., Antson, A. A., Hubbard, R. E., Scott, R. K., & Williams, D. H. (2003). Structure of the Protein Tyrosine Kinase Domain of C-terminal Src Kinase (CSK) in Complexwith Staurosporine. J. Mol. Bi(285), 713–725. papers2://publication/uuid/CBF6FE3B-FE88-4A68-9E4A-EC387CF85D43

Löwenberg, M., Tuynman, J., Bilderbeek, J., Gaber, T., Buttgereit, F., Van Deventer, S., Peppelenbosch, M., & Hommes, D. (2005). Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn. Blood, 106(5), 1703–1710. https://doi.org/10.1182/blood-2004-12-4790

Morisot, N., Berger, A. L., Phamluong, K., Cross, A., & Ron, D. (2019). The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking. Addiction Biology, 24(6), 1227–1234. https://doi.org/10.1111/adb.12699

Nygaard, H. B., Van Dyck, C. H., & Strittmatter, S. M. (2014). Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimer’s Research and Therapy, 6(1), 1–8. https://doi.org/10.1186/alzrt238

Saito, H. (2001). Histidine phosphorylation and two-component signaling in eukaryotic cells. Chemical Reviews, 101(8), 2497–2509. https://doi.org/10.1021/cr000243+

Sen, B., Johnson, F.M., 2011. Regulation of Src Family Kinases in Human Cancers. J. Signal Transduct. 2011, 1–14. https://doi.org/10.1155/2011/865819

St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Weir, M. E., Schmoker, A. M., Ebert, A. M., & Ballif, B. A. (2018). Fyn-dependent phosphorylation of PlexinA1 and PlexinA2 at conserved tyrosines is essential for zebrafish eye development. FEBS Journal, 285(1), 72–86. https://doi.org/10.1111/febs.14313

Toullec, D., Pianetti, P., Coste, H., Bellevergue, P., Grand-Perret, T., Ajakane, M., Baudet, V., Boissin, P., Boursier, E., Loriolle, F., Duhamel, L., Charon, D., & Kirilovsky, J. (1991). The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. Journal of Biological Chemistry, 266(24), 15771–15781. https://doi.org/10.1016/s0021-9258(18)98476-0

Zegzouti, H. et al. (2009) ‘ADP-Glo: A bioluminescent and homogeneous adp monitoring assay for Kinases’, Assay and Drug Development Technologies, 7(6), pp. 560–572. doi: 10.1089/adt.2009.0222.

ZFIN Gene: fyna. (n.d.). Retrieved March 14, 2021, from https://zfin.org/ZDB-GENE-030903-5#phenotype