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STAT5 inhibition leads to Suppression of STAT5 binding to cytokine gene promoters
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response||adjacent||High||High||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
STAT proteins bind with their SH2 domains (which are located between amino acids 600 and 700) to phosphorylated tyrosine residues of transmembrane receptors (Heim, et al. 1995, Stahl, et al. 1995). Once STATs are bound to the receptors, the receptor-associated Jak kinases phosphorylate them on a single tyrosine residue located carboxy terminal of the SH2 domain. Changing this tyrosine to phenylalanine results in STATs that are no longer functional (Shuai, et al. 1993). Two STATs dimerize through specific reciprocal SH2–phosphotyrosine interaction and translocate to the nucleus. After translocation into the nucleus, STATs bind DNA response elements in promoters of target genes. The putative DNA-binding domain lies between amino acids 400 and 500. After DNA binding STATs interact directly or indirectly with the RNA polymerase II complex. The DNA sequence elements in the promoters of genes that bind STAT proteins can be classified in two groups. The prototype of the first class is the interferon-stimulated response element (ISRE).
The second class comprises the GAS-like response elements. STAT5 homodimers have been shown to bind to at least one of the GAS-like elements (Heim 1996).
Evidence Supporting this KER
The observation that STAT5a/STAT5b/double KO mice are defective in IL-2-induced IL-2Rα expression, suggested that STAT5 is essential for this expression (Kim, et al. 2001, Moriggl, et al. 1999).
In another study, CD25 associated with the intermediate affinity IL-2Rβγ subunits to form the high-affinity heterotrimeric IL-2Rαβγ. In response to ligation with IL-2, signaling of the complex through the IL-2Rβγ chains resulted in the phosphorylation of STAT5 (Waldmann 2006).
STAT5a/b mutant peripheral T cells in mice are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression. STAT5 proteins are essential mediators of IL-2 signaling in T cells (Willerford, et al. 1995).
IL-2 binding to CD25 triggers the grouping with IL-2Rβ and γ chains, leading to signal transduction through STAT5, mitogen-activated protein kinase, and phosphoinositide 3-kinases (PI3Ks) (Fujii, et al. 1995, Ravichandran and Burakoff 1994, Remillard, et al. 1991). Within all T cell populations, IL-2 signaling appears to be primarily mediated through phosphorylation of STAT5 (Hirakawa, et al. 2016).
Upon T cell receptor stimulation, IL-2/STAT5 signaling promotes T cell differentiation. This is the first key step in generating effector T cells that can target pathogens (Liao, et al. 2013).
Increasing the concentrations of IL-2 to superphysiological levels (1000 units/mL), which would eliminate the required upregulation of the IL-2 receptor α chain, also failed to induce a proliferative response in cells from Stat5a/b mutant mice (Willerford, et al. 1995).
Splenic lymphocytes from STAT5a/b, but not STAT5a or STAT5b, mutant mice failed to significantly respond to increasing concentrations of IL-2 in the presence of anti-CD3 (Moriggl, et al. 1999).
Uncertainties and Inconsistencies
Inhibition of phosphatase activity by calyculin A treatment of YT cells resulted in a significant induction of serine phosphorylation of JAK3 and STAT5, and serine/threonine phosphorylation of IL-2Rβ. Moreover, inhibition of protein phosphatase 2 (PP2A) diminished IL-2-induced tyrosine phosphorylation of IL-2Rβ, JAK3, and STAT5, and abolished STAT5 DNA binding activity (Ross, et al. 2010).
Known modulating factors
As a property of STAT, it is known that DNA binding ability is acquired by forming a dimer, and it is considered that a modifying factor does not intervene in that respect.
Known Feedforward/Feedback loops influencing this KER
IL-2 acts on the same cell that secretes the cytokine. For instance, IL-2 produced by T cells operates on the same T cells that produce this cytokine, or on neighboring cells. With the highest levels in secondary lymphoid organs, IL-2 is believed to act in an autocrine or paracrine manner to support effector and memory CD8 T cell differentiation (Kalia and Sarkar 2018).
Domain of Applicability
Fujii H, Nakagawa Y, Schindler U, Kawahara A, Mori H, Gouilleux F, Groner B, Ihle JN, Minami Y, Miyazaki T, et al. 1995. Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission. Proc Natl Acad Sci U S A 92:5482-5486. DOI: 10.1073/pnas.92.12.5482.
Gonsky R, Deem RL, Bream J, Young HA, Targan SR. 2004. Enhancer role of STAT5 in CD2 activation of IFN-gamma gene expression. J Immunol 173:6241-6247. DOI: 10.4049/jimmunol.173.10.6241.
Heim MH. 1996. The Jak-STAT pathway: specific signal transduction from the cell membrane to the nucleus. Eur J Clin Invest 26:1-12. DOI: 10.1046/j.1365-2362.1996.103248.x.
Heim MH, Kerr IM, Stark GR, Darnell JE, Jr. 1995. Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267:1347-1349. DOI: 10.1126/science.7871432.
Hirakawa M, Matos TR, Liu H, Koreth J, Kim HT, Paul NE, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J. 2016. Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI Insight 1:e89278. DOI: 10.1172/jci.insight.89278.
Kalia V, Sarkar S. 2018. Regulation of Effector and Memory CD8 T Cell Differentiation by IL-2-A Balancing Act. Front Immunol 9:2987. DOI: 10.3389/fimmu.2018.02987.
Kim HP, Kelly J, Leonard WJ. 2001. The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15:159-172.
Liao W, Lin JX, Leonard WJ. 2013. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:13-25. DOI: 10.1016/j.immuni.2013.01.004.
Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, Grosveld GC, Ihle JN. 1999. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:249-259.
Ravichandran KS, Burakoff SJ. 1994. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem 269:1599-1602.
Remillard B, Petrillo R, Maslinski W, Tsudo M, Strom TB, Cantley L, Varticovski L. 1991. Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem 266:14167-14170.
Ross JA, Cheng H, Nagy ZS, Frost JA, Kirken RA. 2010. Protein phosphatase 2A regulates interleukin-2 receptor complex formation and JAK3/STAT5 activation. J Biol Chem 285:3582-3591. DOI: 10.1074/jbc.M109.053843.
Shuai K, Stark GR, Kerr IM, Darnell JE, Jr. 1993. A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science 261:1744-1746. DOI: 10.1126/science.7690989.
Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE, Jr., Yancopoulos GD. 1995. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267:1349-1353. DOI: 10.1126/science.7871433.
Waldmann TA. 2006. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6:595-601. DOI: 10.1038/nri1901.
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. 1995. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521-530.
Zhang H, Conrad DM, Butler JJ, Zhao C, Blay J, Hoskin DW. 2004. Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. J Immunol 173:932-944. DOI: 10.4049/jimmunol.173.2.932.