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Relationship: 2402

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition of Fyna leads to Inhibition of Plxna2

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Inhibition of Fyna
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Inhibition of Plxna2

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos) adjacent Moderate Low Vid Modic (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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
zebrafish Danio rerio High NCBI
mouse Mus musculus High NCBI
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

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

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Normally, Fyna phosphorylates Plxna2, allowing Plxna2 to effectively bind semaphorin signals. When Fyna is inhibited, the phosphorylation of Plxna2 is inhibited and the Plxna2 function as a semaphorin receptor is inhibited. 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Fyna (Src family tyrosine kinase A) is a non receptor tyrosine. 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). Phosphorylation of certain tyrosine residues changes the enzymatic activity of tyrosine kinases and regulates specificity for substrate binding, localization, and recruitment of downstream signaling proteins (Hanrs & Hunter2, 1995). Plxna2 is one of the Fyna downstream signaling proteins. In mice Fyn was discovered to constitutively associate with and phosphorylate the intracellular region of Plxna1 and Plxna2 (Sasaki et al., 2002).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Fyna (Src family tyrosine kinase A) induces phosphorylation of plexins (plxna2) (Sasaki et al., 2002;St. Clair et al., 2018 ). Inhibition of Fyna leads to reduced Plxna2 phosphorylation and results in inhibition of its activity.

 

  • To show that FYN induces PLXNA2 tyrosine phosphorylation HEK293 cells were transfected with expression plasmids encoding Flag-tagged PLXNA2 and either FYN wild-type (WT) or a kinase dead (KD) point mutant of Fyn. PLXNA2 showed prominent tyrosine phosphorylation when FYN WT was coexpressed and this phosphorylation was absent when FYN KD was coexpressed. These results are consistent with the findings of others (Sasaki et al., 2002) and demonstrate tyrosine phosphorylation events on Plxna2 that are induced by Fyna kinase activity (St. Clair et al., 2018).

  • Using zebrafish as a model organism, (St. Clair et al., 2018) investigated the in vivo functional significance of phosphorylation sites and found that Fyna-dependent Plxna2 phosphorylation is critical for zebrafish eye development. Fyna was shown to induce phosphorylation of two conserved sites on Plxna1 and Plxna2. Y1605 and Y1677 are the major Fyn-dependent sites of Plxna2 tyrosine phosphorylation.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

No known inconsistencies. 

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

No data. 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

No data. 

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

No data. 

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

No data. 

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

KER described here has been established mostly in zebrafish and other vertebrate models. Research suggests that Fyn-dependent phosphorylation is a key feature of vertebrate Plxna1 and Plxna2 signal transduction which is essential for zebrafish eye development (St. Clair et al., 2018).

References

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

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

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

St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Marion, W. 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

Sasaki, Y., Cheng, C., Uchida, Y., Nakajima, O., Ohshima, T., Yagi, T., Taniguchi, M., Nakayama, T., Kishida, R., Kudo, Y., Ohno, S., Nakamura, F., & Goshima, Y. (2002). Fyn and Cdk5 Mediate Semaphorin-3A Signaling, Which Is Involved in Regulation of Dendrite Orientation in Cerebral Cortex drite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regula. Neuron, 35, 907–920.

         ZFIN Gene: plxna2. (n.d.). Retrieved March 15, 2021, from http://zfin.org/ZDB-GENE-090311-6