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Event: 1716

Key Event Title

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

Blockade of STAT5 phosphorylation

Short name
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STAT5 inhibition
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Biological Context

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Level of Biological Organization
Cellular

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

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
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
protein dephosphorylation signal transducer and transcription activator STAT 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 KeyEvent 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

Life Stages

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Life stage Evidence
All life stages 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

The STAT family of proteins regulate gene transcription upon activation. The proteins rely on cytokine signaling and a number of growth factors through the JAK/STAT  pathway (Kisseleva, et al. 2002). STAT activation is regulated by phosphorylation of protein monomers at conserved tyrosine residues, followed by binding to phospho-peptide pockets and subsequent dimerization (Gianti and Zauhar 2015). STAT5 has been implicated in cell growth and differentiation. STAT5 was originally purified and cloned from mammary epithelial cells in sheep and identified as a signal transducer that confers the specific biological responses of prolactin (Wakao, et al. 1992, Xu, et al. 1996).Thus, STAT5 proteins function as signal transduction molecules in the cytoplasm and as transcription factors upon translocation to the nucleus.

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 of STAT5 tyrosine can be detected by specific antibodies using several detection systems, including flow cytometry. In one study, phosphorylated STAT5 expression was measured in T lymphocytes, and MFIs were reported for each subset (Osinalde, et al. 2017). A cell-permeable non-peptidic nicotinoyl hydrazone compound selectively targets the SH2 domain of STAT5 (IC50 = 47 µM against STAT5b SH2 domain EPO peptide binding activity), with markedly less recognition of the SH2 domain of STAT1, STAT3, or Lck (IC50 >500 µM). The compound was reported to block STAT5/STAT5 DNA binding activity in K562 nuclear extract and inhibit IFN-α-stimulated STAT5 tyrosine phosphorylation in Daudi cells, with no effect on STAT1 or STAT3 (Muller, et al. 2008).

Tyrosine phosphorylation of STAT5 induced by IL-2 has been analyzed using an anti-STAT5 antibody. In the study, this antibody immunoprecipitated STAT5 (p94 kDa). Peripheral blood lymphocytes were untreated (control) or treated with IL-2, IL-4, or IL-15 for 15 min. The extracts were incubated with biotinylated oligonucleotide bound to streptavidin-coated agarose. The agarose beads were washed and the eluted protein was immunoblotted with an antibody to STAT5 (Stahl, et al. 1994).

Other authors described the inhibition of JAK3 kinase activity by PF-06651600, followed by inhibition of the phosphorylation of STAT5 elicited by IL-2, IL-4, IL-7, and IL-15 with IC50 values of 244, 340, 407, and 266 nM, respectively (Telliez, et al. 2016).

Pimozide is a specific inhibitor of STAT5 phosphorylation. Pimozide decreased the survival of chronic myelogenous leukemia cells resistant to kinase inhibitors (Nelson, et al. 2011). IL-2 markedly stimulated STAT5 phosphorylation in PBMCs from patients with chronic kidney disease (CKD). Pretreatment with pimozide (3 µM) dramatically suppressed IL-2-induced STAT5 phosphorylation, indicating that it is a potent blocker of IL-2-stimulated STAT5 phosphorylation in PBMCs from CKD patients.

Domain of Applicability

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STAT5 is expressed in hematopoietic cells, including T cells and B cells from humans, rodents, and other mammalian species (Thibault, et al. 2016).

References

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

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.

Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. 2002. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1-24.

Muller J, Sperl B, Reindl W, Kiessling A, Berg T. 2008. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9:723-727. DOI: 10.1002/cbic.200700701.

Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, Terrell S, Klitgaard JL, Santo L, Addorio MR, Ebert BL, Griffin JD, Frank DA. 2011. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 117:3421-3429. DOI: 10.1182/blood-2009-11-255232

blood-2009-11-255232 [pii].

Osinalde N, Sanchez-Quiles V, Blagoev B, Kratchmarova I. 2017. Data on interleukin (IL)-2- and IL-15-dependent changes in IL-2Rbeta and IL-2Rgamma complexes. Data Brief 11:499-506. DOI: 10.1016/j.dib.2017.02.030.

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.

Thibault G, Paintaud G, Legendre C, Merville P, Coulon M, Chasseuil E, Ternant D, Rostaing L, Durrbach A, Di Giambattista F, Buchler M, Lebranchu Y. 2016. CD25 blockade in kidney transplant patients randomized to standard-dose or high-dose basiliximab with cyclosporine, or high-dose basiliximab in a calcineurin inhibitor-free regimen. Transpl Int 29:184-195. DOI: 10.1111/tri.12688.

Wakao H, Schmitt-Ney M, Groner B. 1992. Mammary gland-specific nuclear factor is present in lactating rodent and bovine mammary tissue and composed of a single polypeptide of 89 kDa. J Biol Chem 267:16365-16370.

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.