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Event: 2066

Key Event Title

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

Altered Signaling Pathways

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

Altered Signaling

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

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

Organ term

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
Deposition of energy leads to vascular remodeling	KeyEvent	Cataia Ives (send email)	Open for citation & comment
Deposition of energy leading to bone loss	KeyEvent	Cataia Ives (send email)	Open for citation & comment
Deposition of Energy Leading to Learning and Memory Impairment	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
human	Homo sapiens	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI
mouse	Mus musculus	Moderate	NCBI

Life Stages

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

Life stage	Evidence
All life stages	Moderate

Sex Applicability

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

Term	Evidence
Unspecific	Low

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

Cells receive, process, and transmit signals to respond to their environment via signaling pathways. Signaling pathways are groups of molecules that work together in a cell to control physiological and metabolic processes. Kinases, for example, are important signaling molecules that can phosphorylate other proteins (Svoboda & Reenstra, 2002). Initiation of signaling pathways is an important component of cellular homeostasis including normal cell development and the response to cellular damage from exposure to external stressors (Esbenshade & Duzic, 2006). Signaling pathways are themselves activated by signals and the same signal can lead to different responses depending on the tissue type (Hamada, et al. 2011; Svoboda & Reenstra, 2002). Examples of signals include the activation of receptors to activate transcriptional targets, induction of receptor-ligand interactions and the initiation of cell-cell contact, or cell-extracellular matrix contact (Hunter, 2000). Many signalling pathways are crucial to intercellular communication via membrane receptors that transduce signals into the cell, while others are activated in an intracellular manner (Svoboda & Reenstra, 2002). Altered signalling (i.e., increase/decrease) can lead to different physiological outcomes, meaning that the directionality of the signaling response, determines the end outcome. For example, increase of the PI3K/Akt/mTOR pathway, which under physiological conditions is responsible for regulating the cell cycle, can lead to increased proliferation and decreased apoptosis. However, a decrease expression of this pathway can lead to an increase in apoptosis and decreased proliferation (Porta et al., 2014; Venkatesulu et al., 2018).

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

Method of Measurement	Reference	Description	OECD Approved Assay
Kinase assays	(Svoboda & Reenstra, 2002)	Block kinase with inhibitors to monitor the activity of a kinase of interest.	No
Cell behaviour assays	(Svoboda & Reenstra, 2002)	Signal transduction events of cells are monitored. Cells are exposed to varying levels of signaling proteins and the resulting actions of a cell are observed (changes in structure, cell shape, matrix binding etc.).	No
Ratiometric or single-wavelength dyes	(Svoboda & Reenstra, 2002)	Detects alterations in signal-transduction activities via monitoring changes in detectable wavelengths.	No
Fluorescence microscopy/spectroscopy	(Oksvold et al., 2002)	Measures cell localization, protein interactions, signal propagation, amplification, and integration in the cell in real-time, or upon stimulation.	Yes
Green Fluorescent Protein (GFP)	(Zaccolo and Pozzan, 2000)	GFP assays act as fluorescent reporters but also as a marker of intracellular signalling events i.e. second messengers Ca2+ and cAMP, or for pH in different various cell compartments	No
Fluorescence Resonance Energy Transfer (FRET)	(Bunt and Wouters, 2017)	Assay helps illuminate the interactions between biological molecules	No
Fluorescence recovery after photobleaching (FRAP)	(Svoboda & Reenstra, 2002)	Determines mobility and diffusion of small molecules.	No
Immunoprecipitation	(Svoboda & Reenstra, 2002)	Involves isolating and concentrating a particular protein from mixed samples to detect changes in signalling molecule activity.	Chromatin immunoprecipitation approved for analyzing histone modifications
Immunohistochemistry	(Kurien et al., 2011; Svoboda & Reenstra, 2002)	Northern, western and southern blotting techniques can be used to visualize signal transduction events. For example, antibodies with recognition epitopes can be used to locate active configurations or phosphorylated proteins within a cell or cell lysate.	No
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR)	(Veremeyko et al., 2012; Alwine et al, 1977)	Measures mRNA expression of the gene of interest.	No
Enzyme-linked immunosorbent assay (ELISA)	(Amsen et al., 2009; Engvall & Perlmann, 1972)	Plate-based assay technique using antibodies to detect presence of a protein in a liquid sample. Can be used to identify presence of a protein of interest especially when in low concentrations	No

Domain of Applicability

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

Taxonomic applicability: Altered signaling is applicable to all animals as cell signaling occurs among animal cells. This includes vertebrates such as humans, mice and rats (Nair et al., 2019).

Life stage applicability: This key event is not life stage specific.

Sex applicability: This key event is not sex specific.

Evidence for perturbation by a stressor: Multiple studies show that signaling pathways can be disrupted by many types of stressors including ionizing radiation and altered gravity (Cheng et al., 2020; Coleman et al., 2021; Su et al., 2020; Yentrapalli et al., 2013).

References

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

Alwine, J. C., D. J. Kemp and G. R. Stark (1977), “Method for detection of specific RNAs in agarose gels by transfer to diazobenzyloxymethyl-paper and hybridization with DNA probes”, Proceedings of the National Academy of Sciences of the United States of America, Vol. 74/12, United States National Academy of Sciences, Washington, D.C., https://doi.org/10.1073/pnas.74.12.5350

Amsen, D., de Visser, K. E., and Town, T. (2009), “Approaches to determine expression of inflammatory cytokines”, in Inflammation and Cancer, Humana Press, Totowa, https://doi.org/10.1007/978-1-59745-447-6_5

Bunt, G., and F. S. Wouters (2017), “FRET from single to multiplexed signaling events”, Biophysical reviews, Vol. 9, Springer, London, https://doi.org/10.1007/s12551-017-0252-z

Cheng, Y. P. et al. (2017), “Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats”, Pflugers Archiv European Journal of Physiology, Vol. 469, Springer, New York, https://doi.org/10.1007/s00424-017-1969-z

Coleman, M. A. et al. (2015), “Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes”, American Journal of Physiology - Heart and Circulatory Physiology, Vol. 309/11, American Physiological Society, Rockville, https://doi.org/10.1152/ajpheart.00050.2015

Engvall, E., and P. Perlmann (1972), “Enzyme-Linked Immunosorbent Assay, Elisa”, The Journal of Immunology, Vol. 109/1, American Association of Immunologists, Minneapolis, pp. 129-135

Esbenshade, T. A., and E. Duzic (2006), “Overview of signal transduction”, Current Protocols in Pharmacology, Vol. 31/1, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/0471141755.ph0201s31

Hamada, N. et al. (2011), “Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects”, Current Molecular Pharmacology, Vol. 4/2, Bentham Science Publishers, Sharjah UAE, https://doi.org/10.2174/1874467211104020079

Hunter, T. (2000), “Signaling - 2000 and beyond”, Cell, Vol. 100/1, Cell Press, Cambridge, https://doi.org/10.1016/s0092-8674(00)81688-8

Kurien, B. T. et al. (2011), “An overview of Western blotting for determining antibody specificities for immunohistochemistry”, in Signal Transduction Immunohistochemistry Methods and Protocols, Springer, London, https://doi.org/10.1007/978-1-61779-024-9_3

Nair, A. et al. (2019), “Conceptual Evolution of Cell Signaling”, International journal of molecular sciences, Vol. 20/13, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms20133292

Oksvold, M. P. et al. (2002), “Fluorescent histochemical techniques for analysis of intracellular signaling”, The Journal of Histochemistry and Cytochemistry, Vol. 50/3, SAGE Publications, Thousand Oaks, https://doi.org/10.1177/002215540205000301

Porta, C., C. Paglino and A. Mosca (2014), “Targeting PI3K/Akt/mTOR Signaling in Cancer”, Frontiers in Oncology, Vol. 4, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fonc.2014.00064

Su, Y. T. et al. (2020), “Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats”, Life Sciences, Vol. 243, Elsevier, Amsterdam, https://doi.org/10.1016/j.lfs.2019.117253

Svoboda, K. K. and W. R. Reenstra (2002), “Approaches to studying cellular signaling: a primer for morphologists”, The Anatomical record, Vol. 269/2, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/ar.10074

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to Translational Science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014

Veremeyko, T. et al. (2012), “Detection of microRNAs in microglia by real-time PCR in normal CNS and during neuroinflammation”, Journal of Visualized Experiments: JoVE, Vol. 65, MyJove Corporation, Cambridge, https://doi.org/10.3791/4097

Yentrapalli, R. et al. (2013), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024

Zaccolo, M. and T. Pozzan (2000), “Imaging signal transduction in living cells with GFP-based probes”, IUBMB life, Vol. 49/5, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1080/152165400410218