API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2403

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 Plxna2 leads to Overexpression of rasl11b

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Inhibition of Plxna2
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Overexpression of rasl11b

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 Low 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

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

Inhibition of Plxna2 activity leads to overexpression of rasl11b. 

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

Plexins (Plxns) are semaphorin (Sema) receptors that play important signaling roles, particularly in the developing nervous system and vasculature. It is known that Plexins have an intracellular split GAP (GTPase activating protein) domain that can regulate Ras-family small GTPases (Negishi et al., 2005; Pasterkamp, 2005). Small GTPases act as molecular switches: “on” when GTP-bound, and “off” when GDP-bound (Bos et al., 2007). GAPs increase GTP hydrolysis and thereby increase the “off,” GDP-bound form of the protein. Plxn intracellular GAP domains are inactive when Plxns are in inactive, open conformations. Upon Sema binding, PlxnAs undergo a conformational change, which forms an active GAP domain, in addition to activating downstream effector proteins (He et al., 2009). 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). 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). 

Rasl11b is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases RPC proliferation and eye size (Emerson et al., 2017). Rasl11b is a member of the small GTPase protein family with a high degree of similarity to RAS proteins (Stolle et al., 2007). The Rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues (Pézeron et al., 2008). Ras proteins are well known to be involved in the mitogen-activated protein kinase (MAPK) pathway, therefore, it is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf, leading to decreases in RPC proliferation seen in morphant embryos (Emerson et al., 2017).

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

Rasl11b is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases retinal precursor cells proliferation and eye size (Emerson et al., 2017).

Microarray analysis using RNA extracted from 18 somite zebrafish embryos deficient in either Sema6a or Plxna2 has enabled the identification of several downstream transcriptional targets of Sema6a/Plxna2 signaling during early stages of neuronal development. Further characterization of one of these genes, RAS-like, family 11, member B (rasl11b), revealed its role in regulating retinal progenitor cell (RPC) proliferation. Microarray results indicated that rasl11b has a 2.18 log-fold change (logFC) in sema6a morphants and a 1.58 logFC in plxna2 morphants (Emerson et al., 2017). The microarray results were confirmed in independent experiments, using RT-PCR as readout (Emerson et al., 2017).

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

The relationships described herein have 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 KER description. More help

Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007). GEFs and GAPs: Critical Elements in the Control of Small G Proteins (DOI:10.1016/j.cell.2007.05.018). Cell, 130(2), 385. https://doi.org/10.1016/j.cell.2007.07.001

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) domain structure and classification. https://doi.org/10.1096/fasebj.9.8.7768349

He, H., Yang, T., Terman, J. R., Zhang, X., & Kuriyan, J. (2009). Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. https://doi.org/https://doi.org/10.1073/pnas.0906923106

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

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

Negishi, M., Oinuma, I., & Katoh, H. (2005). Plexins: Axon guidance and signal transduction. Cellular and Molecular Life Sciences, 62(12), 1363–1371. https://doi.org/10.1007/s00018-005-5018-2

Pasterkamp, R. J. (2005). R-Ras fills another GAP in semaphorin signalling. Trends in Cell Biology, 15(2), 61–64. https://doi.org/10.1016/j.tcb.2004.12.005

Pézeron, G., Lambert, G., Dickmeis, T., Strä Hle, U., Dé, F., Rosa, R. M., & Mourrain, P. (2008). Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype. PLoS ONE. https://doi.org/10.1371/journal.pone.0001434

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

Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Cullen, P., & Lorkowski, S. (2007). Cloning, genomic organization, and tissue-specific expression of the RASL11B gene. Biochimica et Biophysica Acta - Gene Structure and Expression, 1769(7–8), 514–524. https://doi.org/10.1016/j.bbaexp.2007.05.005