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Relationship: 964

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

Activation, EGFR leads to Activation, Sp1

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Activation, EGFR

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Activation, Sp1

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

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
human	Homo sapiens	High	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI
dog	Canis lupus familiaris	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed	Low

Life Stage Applicability

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

Term	Evidence
Adult	Low

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

The EGF receptor family comprises 4 members, EGFR (also referred to as ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4, all of which are transmembrane glycoproteins with an extracellular ligand binding site and an intracellular tyrosine kinase domain. Receptor-ligand binding induces dimerization and internalization, subsequently leading to activation of the receptor through autophosphorylation (Higashiyama et al., 2008). Classical EGFR downstream signaling involves activation of Ras which subsequently initiates signal transduction through the Raf-1/MEK/ERK pathway. MAP kinase activation in turn promotes airway epithelial cell proliferation and differentiation (Lemjabbar et al., 2003; Kim et al., 2005; Hackel et al, 1999) and facilitates epithelial wound repair (Burgel, 2004; van Winkle et al., 1997; Allahverdian et al., 2010). EGFR signal transduction via the MAPK cascade also activates the transcription factor Sp1 (Di et al., 2012; Hewson et al., 2004; Lee et al., 2011; Perrais et al., 2002; Barbier et al., 2012; Oyanagi et al, 2016).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

The described mechanism for this KER may specifically apply in the context of increased MUC5AC gene and protein expression, but not to that of MUC5B, another gel-forming mucin associated with mucus hypersecretion in the airways (Wu et al, 2007).

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

Unknown

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

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

Treatment with 20 ng/mL EGF or TGFa for 24 h induced phosphorylation of Sp1, corresponding to a 2-3-fold increase in MUC2 and MUC5AC promoter activity, which was inhibited by 100 nM mithramycin A (a Sp1 inhibitor) (Perrais et al., 2002).

H292 cells infected with IAV at MOI=1 exhibited Sp1 activation as evidenced by a 1.5- to 5-fold increase in band shift and an approx. 3-fold increase in EGFR phosphorylation at 24 h post-infection (Barbier et al., 2012).

In human primary bronchial epithelial cells treated with 10 nM TCDD, Sp1 phosphorylation and MUC5AC promoter activity increased by ca. 2-fold and 4-fold, respectively, and increased promoter activity was abrogated in the presence of the EGFR inhibitor AG1478 (Lee et al., 2011).

In human A549 lung cancer cells treated with 3% cigarette smoke extract for 3 h, Sp1 expression increased approx. 2.5-fold in the nuclear fraction, and this correlated with a significant increase in Sp1-DNA complex formation. Pretreatment of cells with the EGFR inhibitor AG1478 decreased Sp1-DNA binding (Di et al., 2012).

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

Infection of H292 cells with influenza A virus (IVA) at MOI=1 resulted in increased EGFR phosphorylation, peaking at 24 h. This was accompanied by activation of Sp-1 as shown by EMSA (Barbier et al., 2012).

Treatment of primary bronchial epithelial cells with 10 nM TCDD resulted in maximal EGFR phosphorylation after 30 min. TCDD treatment also led to a time-dependent increase in MUC5AC transcriptional promoter activity, peaking between 6 and 12 h. Sp1 involvement was demonstrated by treatment with the Sp1 inhibitor mithramycin A (Lee et al., 2011).

Treatment with 20 ng/mL EGF or TGFa induced phosphorylation of Sp1, corresponding to a 2-3-fold increase in MUC2 and MUC5AC promoter activity, after 24 hours which was inhibited by 100 nM mithramycin A (a Sp1 inhibitor) (Perrais et al., 2002).

Treatment of H292 cells with a combination of 4 ng/mL TGFa and 25 µg/mL polyI:C resulted in a ca. 3-fold increase in EGFR phosphorylation at 1 h. At 12 h, MUC5AC mRNA expression was induced, intracellular MUC5AC protein expression was increased by nearly 30% and secretion of MUC5AC into the cell culture medium rose approx. 4-fold. MUC5AC mRNA expression could be completely abolished by the Sp1 inhibitor mithramycin A (500 nM) (Oyanagi et al., 2016).

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

Unknownkm

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

EGFR-mediated activation of Sp1 was reported in mouse (Hammoud et al., 2009; Lee et al., 2010), rat (Merchant et al., 1995; Mortensen et al., 1997), dog (Ikari et al., 2009; Ford et al., 1997) and human (Di et al., 2012; Hewson et al., 2004; Lee et al., 2011; Perrais et al., 2002; Barbier et al., 2012; Oyanagi et al, 2016).