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Event: 1885

Key Event Title

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

Inhibition of Plxna2

Short name
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Inhibition of Plxna2
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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
optic vesicle

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

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 KeyEvent 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

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Life stage Evidence
Larvae High

Sex Applicability

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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

Plexins (Plxns) are the receptors encoded by the members of the plexin gene family. They are primary transducers of vertebrate semaphorin (Sema) signals. The vertebrate plexins are subdivided into four subfamilies comprising four type A plexins, three type B plexins, plexin C1 (PlEXC1) and plexin D1(Neufeld & Kessler, 2008; Tamagnone et al., 1999). The plexins are transmembrane receptors distinguished by the presence of a split gTPase-activating (gAP) cytoplasmic domain (Oinuma et al., 2004). Semaphorins are members of a large gene family of secreted and membrane-anchored proteins. There are eight subclasses of Semas. Semas 1 and 2 are found in invertebrates, 3–7 are found in vertebrates, and Sema V is found in the genome of non-neurotropic DNA viruses. They were initially characterized as axon guidance factors and are divided into eight subfamilies. The  receptors belonging to the plexin family function as semaphorin receptors (Neufeld & Kessler, 2008). Semas were initially discovered with respect to their role as repulsive guidance cues for migrating axons, although it is now appreciated that they have much broader roles in development. Semas and Plxns have tissue-specific expression patterns, and many Semas can signal through multiple Plxn family members (Luo et al., 1993).

Plxna2 is predicted to have semaphorin receptor activity. Involved in optic vesicle formation, predicted to localize to integral component of plasma membrane and semaphorin receptor complex. Is expressed in several structures, including brain; hatching gland; olfactory field; optic vesicle; and retina and is critical to zebrafish eye development. Orthologous to human PLXNA2 (plexin A2)(ZFIN Gene: Plxna2, n.d.).

Sema-Plxn signaling regulates cellular processes such as cytoskeletal dynamics, proliferation, and differentiation. However, the receptor-proximal signaling mechanisms driving Sema-Plxn signal transduction are only partially understood. Plxn tyrosine phosphorylation is thought to play an important role in these signaling events as receptor and nonreceptor tyrosine kinases have been shown to interact with Plxn receptors (St. Clair et al., 2018). Phosphorylation is one of the fundamental mechanisms of cell signaling and regulation of cell growth, proliferation, differentiation, metabolism, neural function, etc. (Hanrs & Hunter, 1995; Johnson & Lewis, 2010; Mellado et al., 2001). Tyrosine phosphorylation is a pivotal post-translational protein modification that regulates intracellular signalling. Therefore, phosphorylation of tyrosines in the intracellular domain of plex-ins could determine or modify their interactions with additional signal transducers (Franco & Luca Tamagnone, 2008).

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

Phosphorylation changes of Plxna2 tyrosine can be detected  directly using western blot and indirectly by using ELISA method to measure Plxna2 activity. There are several antibodies available commercially. 

In (St. Clair et al., 2018) study, Fyn kinase dependent phosphorylation of plxna2 was measured with western blotting using α-Fyn (rabbit mAb), α-Flag M2 (mouse mAb), α-phosphotyrosine 4G10 (mouse mAb), and α-Src pY416 (rabbit mAb). The following secondary antibodies were used: α-rabbit-HRP (goat IgG), α-mouse-HRP (goat IgG), or for immunoprecipitation samples, α-mouse- HRP Light Chain Specific (goat IgG) .

Domain of Applicability

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

Key event described here has been primarily established in zebrafish models (Emerson et al., 2017; St. Clair et al., 2018).

References

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

Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. Developmental Dynamics, 246(7), 539–549. https://doi.org/10.1002/dvdy.24512

Franco, M., & Luca Tamagnone, &. (2008). review Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Reports, 9, 865–871. https://doi.org/10.1038/embor.2008.139

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

Johnson, L. N., & Lewis, R. J. (2010). ChemInform Abstract: Structural Basis for Control by Phosphorylation. ChemInform, 32(40), no--no. https://doi.org/10.1002/chin.200140284

Luo, Y., Raible, D., & Raper, J. A. (1993). Collapsin : A Protein in Brain That Induces the Collapse and Paralysis of Neuronal Growth Cones. 75(1984), 217–227.

Mellado, M., Rodríguez-Frade, J. M., Mañes, S., & Martínez-A., C. (2001). Chemokine signaling and functional responses: The role of receptor dimerization and TK pathway activation. Annual Review of Immunology, 19, 397–421. https://doi.org/10.1146/annurev.immunol.19.1.397

Neufeld, G., & Kessler, O. (2008). The semaphorins: Versatile regulators of tumour progression and tumour angiogenesis. Nature Reviews Cancer, 8(8), 632–645. https://doi.org/10.1038/nrc2404

Oinuma, I., Ishikawa, Y., Katoh, H., & Negishi, M. (2004). The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science, 305(5685), 862–865. https://doi.org/10.1126/science.1097545

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

Tamagnone, L., Artigiani, S., Chen, H., He, Z., Ming, G. L., Song, H. J., Chedotal, A., Winberg, M. L., Goodman, C. S., Poo, M. M., Tessier-Lavigne, M., & Comoglio, P. M. (1999). Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell, 99(1), 71–80. https://doi.org/10.1016/S0092-8674(00)80063-X

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