This Event 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.

Event: 1715

Key Event Title

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

Inhibition of JAK3

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

Inhibition of JAK3

Explore in a Third Party Tool

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

Cell term
T cell

Organ term

Organ term
immune system

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

Process	Object	Action
regulation of binding	tyrosine-protein kinase JAK3	decreased

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
Immune dysfunction induced by JAK3 inhibition	MolecularInitiatingEvent	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite	Under Development

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
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Rattus rattus	Rattus rattus	High	NCBI

Life Stages

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

Life stage	Evidence
All life stages	High

Sex Applicability

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

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

Janus tyrosine kinase (JAK) 3 is a member of the JAK family that is constitutively associated with the Box-1 region of the cytokine receptor intracellular domain. JAK3 is activated upon ligand-induced receptor dimerization (Stahl, et al. 1994).

The PF-06651600 selective JAK3 inhibitor is undergoing phase 2 clinical evaluation for use in treating rheumatoid arthritis. This compound inhibits JAK3 kinase activity with an IC50 of 33.1 nM (IC50 > 10000 nM). It lacks activity against JAK1, JAK2, or TYK2 (Telliez, et al. 2016, Thorarensen, et al. 2017). The RB1 novel and highly selective JAK3 inhibitor blocks JAK3 kinase in vitro and abrogates functional activity in various cell types (Pei, et al. 2018). When orally administered to mice, RB1 mediate the JAK-STAT pathway and reduces the clinical and microscopic manifestations of paw damage in collagen-induced arthritis mice.

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

Enzymatic activities against JAK1, JAK2, JAK3, and TYK2 were examined using a Caliper Mobility Shift Assay. In the presence of an ATP concentration at Km for ATP for each JAK isoform, RB1 inhibited JAK3 kinase activity with an IC50 value of 40 nM without inhibiting JAK1, JAK2, or TYK2 (IC50 > 5000 nM) (Gianti and Zauhar 2015). The PF-06651600 JAK3 inhibitor displays potent inhibitory activity with an IC50 of 33.1 nM (IC50>10 000 nM), with no activity against JAK1, JAK2, and TYK2. PF-06651600 inhibits the phosphorylation of STAT5 elicited by IL-2, IL-4, IL-7, and IL-15 with an IC50 of 244, 340, 407, and 266 nM, respectively (Telliez, et al. 2016).

Domain of Applicability

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

JAKs are a family of nonreceptor protein tyrosine kinases that are critical for cytokine-receptor-binding-triggered signal transduction through STAT to the nuclei of cells. In mammals, the JAK1, JAK2, and TYK2 kinases are ubiquitously expressed. In contrast, the expression of JAK3 is more restricted. It is predominantly expressed in hematopoietic cells and is highly regulated by cell development and activation (Gaffen, et al. 1995, Xu, et al. 1996). JAK3 is solely activated by type I cytokine receptors, featuring a common γ-chain subunit that is activated by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-7 (Peschon, et al. 1994). Mutations in either the γ chain or JAK3 have been identified as a cause of SCID in humans, which manifests as a depletion of T, B, and NK cells with no other defects (Darnell 1997, Decker, et al. 1997).

Loss-of-function mutations in JAK3 cause autosomal recessive SCID. Defects in this form of SCID are restricted to the immune system, which leads to the development of immunosuppressive JAK inhibitors.

References

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

Darnell JE, Jr. 1997. STATs and gene regulation. Science 277:1630-1635.

Decker T, Kovarik P, Meinke A. 1997. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17:121-134. DOI: 10.1089/jir.1997.17.121.

Gaffen SL, Lai SY, Xu W, Gouilleux F, Groner B, Goldsmith MA, Greene WC. 1995. Signaling through the interleukin 2 receptor beta chain activates a STAT-5-like DNA-binding activity. Proc Natl Acad Sci U S A 92:7192-7196.

Gianti E, Zauhar RJ. 2015. An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures". J Comput Aided Mol Des 29:451-470. DOI: 10.1007/s10822-015-9835-6.

Pei H, He L, Shao M, Yang Z, Ran Y, Li D, Zhou Y, Tang M, Wang T, Gong Y, Chen X, Yang S, Xiang M, Chen L. 2018. Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Sci Rep 8:5273. DOI: 10.1038/s41598-018-23569-y.

Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, Park LS, Ziegler SF, Williams DE, Ware CB, Meyer JD, Davison BL. 1994. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180:1955-1960.

Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, et al. 1994. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263:92-95.

Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A. 2016. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol 11:3442-3451. DOI: 10.1021/acschembio.6b00677.

Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. 2017. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem 60:1971-1993. DOI: 10.1021/acs.jmedchem.6b01694.

Xu BC, Wang X, Darus CJ, Kopchick JJ. 1996. Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J Biol Chem 271:19768-19773.