Interleukin-7 signaling (Homo sapiens)

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12, 1615, 2158263, 627142, 241391417, 23, 2522, 257, 92611, 184, 1922, 2514nucleoplasmcytosolIL7R JAK3AcK9,14,18-p-S10,T11-histone H3 p-STAT5A, p-STAT5BIL2RG p-Y694-STAT5A AcK14,18,79-p-S10,T11-histone H3 IL2RG SOCS2 gene AcK14,18,79-p-S10,T11-histone H3 IL7R ADPSTAT5A p-Y694-STAT5A JAK1 2x(p-STAT5A,p-STAT5B):BRWD1 genep-JAK3 PIK3R2 p-Y449-IL7R PIK3R2 PIK3R1 CISH gene AcK14,18-p-T11-histone H3 AcK9,14-p-S10-histone H3 p-STAT5 dimerIL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2IL7:IL7R:JAK1:IL2RG:JAK3p-Y449-IL7R PIK3R3 p-Y449-IL7R IL7R p-Y449-IL7R Immunoglobulin kappalocusADPp-Y694-STAT5A JAK1 IL7 PIK3R1 ATPSOCS1 gene IL2RG IL7IL7R p-STAT5 dimerAcK9,14-p-S10-HIST2H3A p-JAK3 p-JAK3 IL2RG IL2RGIRS2 RAG1:RAG2recombinase:Immunoglobulin kappa locusp-STAT3AcK14,18,79-p-S10-histone H3 IL7RSOCS1 gene TSLP p-Y699-STAT5B IRS1 STAT5B IL7R:TSLP:CRLF2:p-STAT3IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsJAK1 TSLP IL7 p-JAK3 p-Y694-STAT5A p-Y694-STAT5A IRS1,IRS2IL7 p-Y699-STAT5B CRLF2 JAK1 TSLPIL7 ADPJAK3 p-JAK3 CISH gene, SOCS1gene, SOCS2gene:p-STAT5 dimerIL2RG SMARCA4 JAK1 AcK14,18,79-p-T11-histone H3 JAK3 STAT3 STAT5B SMARCA4AcK9,14-p-S10-histone H3 AcK14,18-p-S10,T11-histone H3 IL2RG SOCS2 PIK3R1 p-Y699-STAT5B AcK9,14,18,79-p-S10,T11-histone H3 AcK14,18,79-p-S10-histone H3 PIK3R3 IRS2 ATPJAK1 IL7R:JAK1AcK9,14,18,79-p-S10,T11-histone H3 IL7R BRWD1AcK14,18-p-T11-histone H3 JAK1 BRWD1:AcK(9,14,18,79)-p(S10,T11)-histone H3AcK9,14-p-S10-HIST1H3A BRWD1:SMARCA4IL2RG:JAK3IL7 STAT5A AcK14,18-p-S10,T11-histone H3 CISH AcK(9,14,18,79)-p(S10,T11)-histone H3IL2RG CISH gene, SOCS1gene, SOCS2 geneBRWD1 AcK14,18-p-S10-histone H3 IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5BBRWD1 IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3SOCS2 gene IL7 AcK9,14,18-p-S10,T11-histone H3 RAG2 p-Y694-STAT5A BRWD1:AcK9,14-pS10-histone H3PIK3R3 BRWD1 CRLF2 Immunoglobulin kappa locus IRS1 STAT5A,STAT5BIL7:IL7R:JAK1:IL2RG:p-JAK3CRLF2:IL7RATPJAK1 RAG2 JAK1 IL7R PI3K regulatorysubunitsIL7 RAG1 RAG1 JAK1CRLF2 CISH gene STAT3CRLF2 BRWD1 gene p-Y699-STAT5B AcK14,18-p-S10-histone H3 IL7 HGF(495-728) ATPHGF(495-728):IL7BRWD1 geneIL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5BSOCS1 p-Y699-STAT5B p-Y699-STAT5B HGF(495-728)IL7R IL7 ADPp-Y449-IL7R RAG1:RAG2recombinaseIL2RG IL7R:TSLP:CRLF2:STAT3PIK3R2 IL7R CISH,SOCS1,SOCS2IL7:IL7R:JAK1TSLP AcK14,18,79-p-T11-histone H3 p-STAT3 p-JAK3 IL7R:TSLP:CRLF277710267101075107715771, 201097267147781077771, 207914


Description

Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).

The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7R, IL7RA, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7R is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while IL2RG is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. IL2RG consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of IL2RG in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers, Il2rg knockout mice also have dramatically reduced B-cell populations suggesting that Il2rg is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7R mutations (see Puel & Leonard 2000), or a partial deficiency of IL7R (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of IL2RG mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).

IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7R was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).

The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7R Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).

The model for IL7 receptor signaling is believed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the IL2RG chain. Extending this model to IL7 suggests a similar series of events: IL7R constitutively associated with JAK1 binds IL7, the resulting trimer recruits IL2RG:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7R. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.

The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).

It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1266695
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Ray, KP

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Ontology Terms

 

Bibliography

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  1. Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMed Europe PMC
  2. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMed Europe PMC
  3. Wei C, Lai L, Goldschneider I.; ''Pre-pro-B cell growth-stimulating factor (PPBSF) upregulates IL-7Ralpha chain expression and enables pro-B cells to respond to monomeric IL-7.''; PubMed Europe PMC
  4. Nelson BH, Lord JD, Greenberg PD.; ''Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.''; PubMed Europe PMC
  5. Huang H, Rambaldi I, Daniels E, Featherstone M.; ''Expression of the Wdr9 gene and protein products during mouse development.''; PubMed Europe PMC
  6. Lai L, Goldschneider I.; ''Cutting edge: Identification of a hybrid cytokine consisting of IL-7 and the beta-chain of the hepatocyte growth factor/scatter factor.''; PubMed Europe PMC
  7. Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S.; ''Histone recognition and large-scale structural analysis of the human bromodomain family.''; PubMed Europe PMC
  8. Sharfe N, Roifman CM.; ''Differential association of phosphatidylinositol 3-kinase with insulin receptor substrate (IRS)-1 and IRS-2 in human thymocytes in response to IL-7.''; PubMed Europe PMC
  9. Mandal M, Hamel KM, Maienschein-Cline M, Tanaka A, Teng G, Tuteja JH, Bunker JJ, Bahroos N, Eppig JJ, Schatz DG, Clark MR.; ''Histone reader BRWD1 targets and restricts recombination to the Igk locus.''; PubMed Europe PMC
  10. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMed Europe PMC
  11. Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMed Europe PMC
  12. Kondo M, Takeshita T, Higuchi M, Nakamura M, Sudo T, Nishikawa S, Sugamura K.; ''Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes.''; PubMed Europe PMC
  13. Goodwin RG, Friend D, Ziegler SF, Jerzy R, Falk BA, Gimpel S, Cosman D, Dower SK, March CJ, Namen AE.; ''Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily.''; PubMed Europe PMC
  14. Reche PA, Soumelis V, Gorman DM, Clifford T, Liu Mr, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal Malefyt R, Kastelein RA, Bazan JF.; ''Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.''; PubMed Europe PMC
  15. Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S.; ''The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.''; PubMed Europe PMC
  16. Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ.; ''Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor.''; PubMed Europe PMC
  17. Yu CR, Young HA, Ortaldo JR.; ''Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells.''; PubMed Europe PMC
  18. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMed Europe PMC
  19. Zhu MH, Berry JA, Russell SM, Leonard WJ.; ''Delineation of the regions of interleukin-2 (IL-2) receptor beta chain important for association of Jak1 and Jak3. Jak1-independent functional recruitment of Jak3 to Il-2Rbeta.''; PubMed Europe PMC
  20. Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMed Europe PMC
  21. Cheng Y, Chikwava K, Wu C, Zhang H, Bhagat A, Pei D, Choi JK, Tong W.; ''LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors.''; PubMed Europe PMC
  22. Foxwell BM, Beadling C, Guschin D, Kerr I, Cantrell D.; ''Interleukin-7 can induce the activation of Jak 1, Jak 3 and STAT 5 proteins in murine T cells.''; PubMed Europe PMC
  23. Juffroy O, Bugault F, Lambotte O, Landires I, Viard JP, Niel L, Fontanet A, Delfraissy JF, Thèze J, Chakrabarti LA.; ''Dual mechanism of impairment of interleukin-7 (IL-7) responses in human immunodeficiency virus infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway.''; PubMed Europe PMC
  24. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC
  25. van der Plas DC, Smiers F, Pouwels K, Hoefsloot LH, Löwenberg B, Touw IP.; ''Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain.''; PubMed Europe PMC
  26. Ghazawi FM, Faller EM, Parmar P, El-Salfiti A, MacPherson PA.; ''Suppressor of cytokine signaling (SOCS) proteins are induced by IL-7 and target surface CD127 protein for degradation in human CD8 T cells.''; PubMed Europe PMC
  27. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA.; ''Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101404view11:29, 1 November 2018ReactomeTeamreactome version 66
100942view21:05, 31 October 2018ReactomeTeamreactome version 65
100479view19:39, 31 October 2018ReactomeTeamreactome version 64
100024view16:22, 31 October 2018ReactomeTeamreactome version 63
99577view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99199view12:43, 31 October 2018ReactomeTeamreactome version 62
94021view13:52, 16 August 2017ReactomeTeamreactome version 61
93640view11:29, 9 August 2017ReactomeTeamreactome version 61
86957view13:26, 15 July 2016MkutmonOntology Term : 'interleukin-7 signaling pathway' added !
86755view09:25, 11 July 2016ReactomeTeamreactome version 56
83273view10:37, 18 November 2015ReactomeTeamVersion54
81389view12:55, 21 August 2015ReactomeTeamVersion53
76857view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76562view11:54, 16 July 2014ReactomeTeamFixed remaining interactions
75895view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75595view10:44, 10 June 2014ReactomeTeamReactome 48 Update
74950view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74594view08:38, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2x(p-STAT5A,p-STAT5B):BRWD1 geneComplexR-HSA-8865622 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AcK(9,14,18,79)-p(S10,T11)-histone H3ComplexR-HSA-8871307 (Reactome)
AcK14,18,79-p-S10,T11-histone H3 R-HSA-8871287 (Reactome)
AcK14,18,79-p-S10-histone H3 R-HSA-8871272 (Reactome)
AcK14,18,79-p-T11-histone H3 R-HSA-8871284 (Reactome)
AcK14,18-p-S10,T11-histone H3 R-HSA-8871291 (Reactome)
AcK14,18-p-S10-histone H3 R-HSA-8871297 (Reactome)
AcK14,18-p-T11-histone H3 R-HSA-8871301 (Reactome)
AcK9,14,18,79-p-S10,T11-histone H3 R-HSA-8865599 (Reactome)
AcK9,14,18-p-S10,T11-histone H3 R-HSA-8871305 (Reactome)
AcK9,14-p-S10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
AcK9,14-p-S10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
AcK9,14-p-S10-histone H3 R-HSA-8870890 (Reactome)
BRWD1 ProteinQ9NSI6 (Uniprot-TrEMBL)
BRWD1 gene ProteinENSG00000185658 (Ensembl)
BRWD1 geneGeneProductENSG00000185658 (Ensembl)
BRWD1:AcK(9,14,18,79)-p(S10,T11)-histone H3ComplexR-HSA-8865594 (Reactome)
BRWD1:AcK9,14-pS10-histone H3ComplexR-HSA-8870891 (Reactome)
BRWD1:SMARCA4ComplexR-HSA-8865593 (Reactome)
BRWD1ProteinQ9NSI6 (Uniprot-TrEMBL)
CISH ProteinQ9NSE2 (Uniprot-TrEMBL)
CISH gene ProteinENSG00000114737 (Ensembl)
CISH gene, SOCS1

gene, SOCS2

gene:p-STAT5 dimer
ComplexR-HSA-9012668 (Reactome)
CISH gene, SOCS1 gene, SOCS2 geneComplexR-HSA-9006971 (Reactome)
CISH,SOCS1,SOCS2ComplexR-HSA-9006972 (Reactome)
CRLF2 ProteinQ9HC73 (Uniprot-TrEMBL)
CRLF2:IL7RComplexR-HSA-8982873 (Reactome)
HGF(495-728) ProteinP14210 (Uniprot-TrEMBL)
HGF(495-728):IL7ComplexR-HSA-1266704 (Reactome)
HGF(495-728)ProteinP14210 (Uniprot-TrEMBL)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL2RG:JAK3ComplexR-HSA-451911 (Reactome)
IL2RGProteinP31785 (Uniprot-TrEMBL)
IL7 ProteinP13232 (Uniprot-TrEMBL)
IL7:IL7R:JAK1:IL2RG:JAK3ComplexR-HSA-449967 (Reactome)
IL7:IL7R:JAK1:IL2RG:p-JAK3ComplexR-HSA-9025934 (Reactome)
IL7:IL7R:JAK1ComplexR-HSA-449983 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2ComplexR-HSA-8982992 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5BComplexR-HSA-9025978 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5BComplexR-HSA-8982988 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3ComplexR-HSA-1295546 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsComplexR-HSA-1295544 (Reactome)
IL7ProteinP13232 (Uniprot-TrEMBL)
IL7R ProteinP16871 (Uniprot-TrEMBL)
IL7R:JAK1ComplexR-HSA-1264843 (Reactome)
IL7R:TSLP:CRLF2:STAT3ComplexR-HSA-8982893 (Reactome)
IL7R:TSLP:CRLF2:p-STAT3ComplexR-HSA-8982894 (Reactome)
IL7R:TSLP:CRLF2ComplexR-HSA-8982872 (Reactome)
IL7RProteinP16871 (Uniprot-TrEMBL)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1,IRS2ComplexR-HSA-74698 (Reactome) The proteins mentioned here are examples of IRS family members acting as indicated for IRS.
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
Immunoglobulin kappa locusR-HSA-8865710 (Reactome)
Immunoglobulin kappa locus R-HSA-8865710 (Reactome)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK1ProteinP23458 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
JAK3ProteinP52333 (Uniprot-TrEMBL)
PI3K regulatory subunitsComplexR-HSA-1295511 (Reactome) There are five variants of the PI3K regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta and p55gamma (there are also three variants of the p110 catalytic subunit designated p110alpha, beta, or delta). The first three regulatory subunits are all splice variants of PIK3R1 (p85 or regulatory subunit alpha), the other two are expressed by PIK3R2 and PIK3R3, known as p85 beta, and p55 gamma, respectively. The most highly expressed regulatory subunit is p85alpha. The 3 variants forms of p85 alpha are not explicitly represented in this set.
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
RAG1 ProteinP15918 (Uniprot-TrEMBL)
RAG1:RAG2 recombinase:Immunoglobulin kappa locusComplexR-HSA-8865712 (Reactome)
RAG1:RAG2 recombinaseComplexR-HSA-8865713 (Reactome)
RAG2 ProteinP55895 (Uniprot-TrEMBL)
SMARCA4 ProteinP51532 (Uniprot-TrEMBL)
SMARCA4ProteinP51532 (Uniprot-TrEMBL)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS1 gene ProteinENSG00000185338 (Ensembl)
SOCS2 ProteinO14508 (Uniprot-TrEMBL)
SOCS2 gene ProteinENSG00000120833 (Ensembl)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT3ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5A,STAT5BComplexR-HSA-452094 (Reactome)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
TSLP ProteinQ969D9 (Uniprot-TrEMBL)
TSLPProteinQ969D9 (Uniprot-TrEMBL)
p-JAK3 ProteinP52333 (Uniprot-TrEMBL)
p-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-STAT3ProteinP40763 (Uniprot-TrEMBL)
p-STAT5 dimerComplexR-HSA-507919 (Reactome)
p-STAT5 dimerComplexR-HSA-508012 (Reactome)
p-STAT5A, p-STAT5BComplexR-HSA-507929 (Reactome)
p-Y449-IL7R ProteinP16871 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2x(p-STAT5A,p-STAT5B):BRWD1 geneArrowR-HSA-8865626 (Reactome)
2x(p-STAT5A,p-STAT5B):BRWD1 geneTBarR-HSA-8865693 (Reactome)
ADPArrowR-HSA-1295519 (Reactome)
ADPArrowR-HSA-1295540 (Reactome)
ADPArrowR-HSA-8983059 (Reactome)
ADPArrowR-HSA-8983063 (Reactome)
ATPR-HSA-1295519 (Reactome)
ATPR-HSA-1295540 (Reactome)
ATPR-HSA-8983059 (Reactome)
ATPR-HSA-8983063 (Reactome)
AcK(9,14,18,79)-p(S10,T11)-histone H3R-HSA-8865613 (Reactome)
BRWD1 geneR-HSA-8865626 (Reactome)
BRWD1 geneR-HSA-8865693 (Reactome)
BRWD1:AcK(9,14,18,79)-p(S10,T11)-histone H3ArrowR-HSA-8865613 (Reactome)
BRWD1:AcK9,14-pS10-histone H3ArrowR-HSA-8865711 (Reactome)
BRWD1:SMARCA4ArrowR-HSA-8865605 (Reactome)
BRWD1ArrowR-HSA-8865693 (Reactome)
BRWD1R-HSA-8865605 (Reactome)
BRWD1R-HSA-8865613 (Reactome)
CISH gene, SOCS1

gene, SOCS2

gene:p-STAT5 dimer
ArrowR-HSA-8983011 (Reactome)
CISH gene, SOCS1

gene, SOCS2

gene:p-STAT5 dimer
ArrowR-HSA-9012671 (Reactome)
CISH gene, SOCS1 gene, SOCS2 geneR-HSA-8983011 (Reactome)
CISH gene, SOCS1 gene, SOCS2 geneR-HSA-9012671 (Reactome)
CISH,SOCS1,SOCS2ArrowR-HSA-8983011 (Reactome)
CRLF2:IL7RR-HSA-8983061 (Reactome)
HGF(495-728):IL7ArrowR-HSA-1266684 (Reactome)
HGF(495-728)R-HSA-1266684 (Reactome)
IL2RG:JAK3ArrowR-HSA-451895 (Reactome)
IL2RG:JAK3R-HSA-449958 (Reactome)
IL2RGR-HSA-451895 (Reactome)
IL7:IL7R:JAK1:IL2RG:JAK3ArrowR-HSA-449958 (Reactome)
IL7:IL7R:JAK1:IL2RG:JAK3R-HSA-8983063 (Reactome)
IL7:IL7R:JAK1:IL2RG:JAK3mim-catalysisR-HSA-8983063 (Reactome)
IL7:IL7R:JAK1:IL2RG:p-JAK3ArrowR-HSA-8983063 (Reactome)
IL7:IL7R:JAK1:IL2RG:p-JAK3R-HSA-1295519 (Reactome)
IL7:IL7R:JAK1:IL2RG:p-JAK3mim-catalysisR-HSA-1295519 (Reactome)
IL7:IL7R:JAK1ArrowR-HSA-449978 (Reactome)
IL7:IL7R:JAK1R-HSA-449958 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2ArrowR-HSA-8983003 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5BArrowR-HSA-9025969 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5BR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5Bmim-catalysisR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5BArrowR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5BR-HSA-6785165 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3ArrowR-HSA-1295519 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3ArrowR-HSA-6785165 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3R-HSA-1295516 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3R-HSA-9025969 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsArrowR-HSA-1295516 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsR-HSA-8983003 (Reactome)
IL7R-HSA-1266684 (Reactome)
IL7R-HSA-449978 (Reactome)
IL7R:JAK1ArrowR-HSA-1264832 (Reactome)
IL7R:JAK1R-HSA-449978 (Reactome)
IL7R:TSLP:CRLF2:STAT3ArrowR-HSA-8983077 (Reactome)
IL7R:TSLP:CRLF2:STAT3R-HSA-8983059 (Reactome)
IL7R:TSLP:CRLF2:STAT3mim-catalysisR-HSA-8983059 (Reactome)
IL7R:TSLP:CRLF2:p-STAT3ArrowR-HSA-8983059 (Reactome)
IL7R:TSLP:CRLF2:p-STAT3R-HSA-8983078 (Reactome)
IL7R:TSLP:CRLF2ArrowR-HSA-8983061 (Reactome)
IL7R:TSLP:CRLF2ArrowR-HSA-8983078 (Reactome)
IL7R:TSLP:CRLF2R-HSA-8983077 (Reactome)
IL7RR-HSA-1264832 (Reactome)
IRS1,IRS2R-HSA-8983003 (Reactome)
Immunoglobulin kappa locusR-HSA-8865711 (Reactome)
JAK1R-HSA-1264832 (Reactome)
JAK3R-HSA-451895 (Reactome)
PI3K regulatory subunitsR-HSA-1295516 (Reactome)
R-HSA-1264832 (Reactome) Interleukin-7 receptor (IL7R) has a small juxta-membrane region known as the Box1 motif, which is conserved throughout the type 1 cytokine receptor family (Murakami et al. 1991) and believed to be the site of JAK1 binding (Tanner et al. 1995). Deletion of the Box1 region of IL7R eliminates JAK1 phosphorylation (Jiang et al. 2004). Studies using mutant Interleukin-4/Interleukin-7 chimeric receptors found that loss of Box1 resulted in rapid cell death, while Y449F mutation causes cell cycle arrest that precedes cell death (Jiang et al. 2004). Mice expressing a knock-in mutation (IL7R Y449F) displayed defective homeostatic proliferation of naive CD4 and CD8 T-cells (Osbourne et al. 2007). The Y449 site is thus of particular interest because two critical Interleukin-7 signaling pathways, the JAK/STAT pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway may originate from this site (Pallard et al. 1999).
R-HSA-1266684 (Reactome) The pre-pro-B cell growth-stimulating factor (PPBSF) is a self-assembling complex of Interleukin-7 (IL7 or IL-7) and a variant beta-chain of hepatocyte growth factor (HGFbeta) (Lai & Goldschneider 2001). This 55 kDa heterodimer, unlike monomeric IL7, selectively stimulates proliferation and differentiation of pre-pro-B cells in a long-term bone marrow culture system and up-regulates Interleukin-7 receptor alpha chain (IL7R) expression on pre-pro-B cell surface. It has been postulated that PPBSF is the active form of IL7 that normally induces IL7R-low pre-pro-B cells to proliferate and differentiate into IL7R-high pro-B cells, which then proliferate and differentiate into pre-B-cells on stimulation with monomeric IL7 (Wei et al. 2002).
R-HSA-1295516 (Reactome) Inferred from mouse:
The p85 subunit of PI3-kinase (PI3K) binds to phosphorylated Tyrosine-449 (Y449) on IL7R.
Y449F substitution inhibits PI3K-dependent proliferation of IL7-stimulated murine B-lineage cells (Venkitaraman & Cowling 1994). Stimulation of human lymphocyte precursor cells with IL7 induced tyrosine phosphorylation of the p85 subunit of PI3K and activation of PI3K kinase activity (Dadi et al. 1994). It is thought that, depending on species differences and stage of lymphocyte development, IL7 induced PI3K pathway can promote signals that are important for survival and proliferation of both T cells and B cells. Activation of PI3K leads to the generation of membrane associated PIP3 and membrane recruitment of AKT/PKB, the key downstream target of PI3K. AKT mediates phosphorylation of downstream substrates involved in regulation of cell survival and proliferation. IL7 induced activation of PI3K/AKT in human thymocytes has been reported (Pallard et al. 1999; Johnson et al. 2008). In mouse thymocytes IL7 stimulation resulted in the inactivation of BAD by serine phosphorylation; the PI3K/AKT pathway has been implicated in BAD phosphorylation. These results suggest that IL7 signaling via AKT inactivates the pro-apoptotic protein BAD promoting T cell survival (Li et al. 2004).

Rochman et al. (2009) suggested that IL7 promotes lymphocyte survival by activating the pro-survival PI3K/AKT signaling pathway and by increasing the expression of survival factors such as BCL2 and myeloid cell leukemia sequence 1 (MCL-1) while inhibiting the expression of pro-apoptotic factors BAX and BAD.
Interleukin-7 induced PI3K-dependent phosphorylation of AKT1 (Akt1 or PKB) and its downstream targets GSK-3, FOXO1, and FOXO3a (Barata et al.2004).

R-HSA-1295519 (Reactome) Interleukin-7 (IL7) signaling is believed to resemble that of other gammaC family receptors, based on detailed studies of the Interleukin-2 receptor. Extending this model to IL7 suggested a series of events that bring Tyrosine-protein kinase JAK1 (JAK1) and Tyrosine-protein kinase JAK3 (JAK3) into proximity within a complex IL7:IL7R:JAK1:IL2RG:JAK3. Cytoplasmic domains of the receptor chains re-orient so that their associated kinases (JAKs and possibly phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). Tyrosine-449 (Y449) in the cytoplasmic domain of Interleukin-7 receptor is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999).
It has been sugggested that JAK1 phosphorylates IL7R (Jiang et al. 2004) and it is believed that JAK3, associated with IL2RG, phosphorylates the tyrosine residues in the cytoplasmic portion of IL7R that lead to recruitment of STATs (Fry & Mackall 2002). This is consistent with the lack of intrinsic tyrosine kinase activity in IL7R:JAK1 in the absence of IL2RG:JAK3 (Lai et al. 1996). Phosphorylated Y449 is believed to be the docking site for STAT5 and possibly PI3K, which are then activated by JAKs (Lin et al. 1995, Jiang et al. 2004). T-cells from IL7R Y449F knock-in mice did not activate Signal transducer and activator of transcription A or B (STAT5A, STAT5B) (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine.
R-HSA-1295540 (Reactome) Signal transducer and activator of transcription 5A or 5B (STAT5A and/or STAT5B, typically referred to as STAT5) are phosphorylated after Interleukin‑7 (IL7) ligand‑receptor interaction (Foxwell et al. 1995, van der Plas et al. 1996, Yu et al. 1998, Jufrroy et al. 2010, Landires et al. 2011).

STAT5 is activated in COS7 cells when co‑transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 phosphorylates STAT5 proteins in response to IL7 in vivo (Lin & Leonard, 2000). STAT5 phosphorylation is represented here as a black box event because it is not clear which JAK kinase phosphorylates STAT5 in vivo.
R-HSA-449958 (Reactome) Studies using chemical crosslinking and monoclonal antibodies specific for Cytokine receptor common subunit gamma (IL2RG) demonstrated that it participates in the functional high-affinity interleukin-7 receptor complex (Noguchi et al. 1993, Kondo et al. 1994).
IL2RG interacts with the intermediate 1:1 IL7:IL7R complex, forming the active ternary complex, which binds Interleukin-7 (IL7) with a 3-fold higher affinity (Kd =80 pM).
R-HSA-449978 (Reactome) Interleukin-7 receptor alpha chain (IL7R) binds interleukin-7 (IL7), forming a stable 1:1 IL7:IL7R complex, with a dissociation constant (Kd) of approximately 200 pM (Goodwin et al. 1990, Park et al. 1990). The full-length Interleukin-7 receptor alpha is a 439-residue single-pass transmembrane glycoprotein consisting of three domains: a 219-residue extracellular domain (ECD), a 25-residue transmembrane domain and a 195-residue cytoplasmic domain. The ECD belongs to the cytokine receptor homology class 1 (CRH1) family, consisting of two fibronectin type III (FNIII) domains with three potential disulfide bonds in the N-terminal FNIII domain and a WSXWS primary sequence motif in the C-terminal domain (Bazan 1990). Recruitment of kinases to the cytoplasmic tail of IL7R is required for signal transduction because the intracellular portion of IL7R does not contain intrinsic tyrosine kinase activity. IL7 interacts directly with the extracellular region of IL7R and this leads to the recruitment of the Cytokine receptor common subunit gamma (IL2RG, Gc) and formation of a receptor complex. IL7 binds glycosylated IL7R 300-fold more tightly than unglycosylated. It is thought that IL7 interacts with both IL7R and IL2RG in the final complex (McElroy et al. 2007).
R-HSA-451895 (Reactome) Cytokine receptor common gamma subunit (IL2RG, IL-2 receptor gamma chain, Gc) associates with Tyrosine-protein kinase JAK3 (JAK3). The carboxyl-terminal region of IL2RG is important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994) as well as the FERM domain in JAK3 (Zhou et al. 2001).
R-HSA-452102 (Reactome) Phosphorylated STAT5A and STAT5B form homodimers and heterodimers in the cytosol (Gaffen et al. 1996, Rosenthal et al. 1997, also inferred from mouse homologs). Phosphorylation of a critical tyrosine residue in the SH domain (Y694 in STAT5A and Y699 in STAT5B) and intramolecular interactions between hydrophobic residues in the SH domain are required for dimerization (inferred from mouse homologs).
R-HSA-507937 (Reactome) Interleukin-7 (IL7)-activated Signal transducer and activator of transcription 5A or 5B (typically referred to as STAT5) is recruited rapidly to the promoters of IL7-regulated genes (Ye et al. 2001, Stanton & Brodeur 2005).
R-HSA-6785165 (Reactome) Signal transducer and activator of transcription 5A or 5B (STAT5A and/or STAT5B, typically referred to as STAT5) are phosphorylated after Interleukin‑7 (IL7) ligand‑receptor interaction (Foxwell et al. 1995, van der Plas et al. 1996, Yu et al. 1998, Jufrroy et al. 2010, Landires et al. 2011).

Interleukin-7 (IL7)-activated Signal transducer and activator of transcription 5A or 5B (typically referred to as STAT5) translocates to the nucleus (Landires et al. 2011) and is recruited rapidly to the promoters of IL7-regulated genes (Ye et al. 2001, Stanton & Brodeur 2005).

This is a black box event because dissociation is inferred from the subsequent translocation of STAT5 to the nucleus.
R-HSA-8865605 (Reactome) BRWD1 (WDR9) is a nuclear protein with eight WD repeats at the N-terminus and 2 centrally located bromodomains. BRWD1 is thought to be involved in chromatin remodelling and transcriptional regulation. BRWD1 binds to Transcription activator BRG1 (SMARCA4 or BRG1), a component of the SWI/SNF complex(Huang et al. 2003). Similar to BRWD1 (Mandal et al. 2015), SMARCA4 is also implicated in B-cell development (Choi et al. 2012, Bossen et al. 2015).
R-HSA-8865613 (Reactome) Human Bromodomain and WD repeat-containing protein 1 (BRWD1) binds to histone H3 acetylated at lysine residues K9, K14, K18 and K79 and phosphorylated at serine residue S10 and threonine residue T11 in various combinations in vitro (Filippakopoulos et al. 2012). In mouse, it was confirmed that BRWD1 interacts with histone H3 acetylated at lysine residues K9 and K14, and phosphorylated at serine residue S10 (Mandal et al. 2015). Please note that the listed amino acid residues in mature histone H3 match nascent histone H3 residues K10, K15, K19, K80, S11 and T12, respectively. Amino acid positions in Reactome annotations of modified residues and Reactome systematic names correspond to positions in the nascent protein UniProt sequence.
R-HSA-8865626 (Reactome) Based on mouse studies Signal transducer and activator of transcription 5A or 5B (STAT5A or STAT5B), activated as a result of interleukin-7 (IL7) signaling, binds to the Bromodomain and WD repeat-containing protein 1 (BRWD1) promoter in pro-B cells (Mandal et al. 2015).
R-HSA-8865693 (Reactome) Based on a mouse model study of pro-B cells, binding of Signal transducer and activator of transcription 5A and 5B (STAT5A or STAT5B), activated in response to Interleukin-7 (IL7) signaling to the BRWD1 gene promoter, results in the inhibition of Bromodomain and WD repeat-containing protein 1 (BRWD1) transcription. STAT5 binding coincides with the appearance of H3K27me3 marks at the BRWD1 promoter, a marker of repressed chromatin (Mandal et al. 2015). STAT5 is able to recruit the polycomb repressive complex (PRC2) to genes silenced in response to IL7 signaling (Mandal et al. 2011), which may explain the H3K27me3 marks at STAT5-bound BRWD1 promoter.

In pre-B cells, in contrast to pro-B cells, IL7 signaling is downregulated, which induces BRWD1 transcription. BRWD1 enhances the recruitment of the recombinase complex V(D)J recombination-activating protein 1: V(D)J recombination-activating protein 2 (RAG1:RAG2) to the immunoglobulin kappa locus, thus promoting V(D)J recombination - a key event in B lymphopoiesis (Mandal et al. 2015).

R-HSA-8865711 (Reactome) Based on studies in mice, Bromodomain and WD repeat-containing protein 1 (BRWD1) is recruited to the Immunoglobulin kappa (IgK) locus through interaction with histone H3 acetylated at lysine residues K9 and K14 and phosphorylated at serine residue S10. ERK is implicated in histone H3 serine S10 phosphorylation at the IGK locus. BRWD1 enhances the recruitment of the RAG1:RAG2 recombinase complex to the IgK locus and positions it at recombination signal sequences within the IgK locus by proper positioning of the nucleosomes, in order for the V(D)J recombination to occur (Mandal et al. 2015). Please note that the listed amino acid residues in mature histone H3 match nascent histone H3 residues K10, K15 and S11, respectively. Amino acid positions in Reactome annotations of modified residues and Reactome systematic names correspond to positions in the nascent protein UniProt sequence.
R-HSA-8983003 (Reactome) Insulin receptor substrate 1 and 2 (IRS1, IRS2) bind to activated Interleukin-7 receptor complex . Interleukin-7 (IL7) stimulation of human thymocytes results in the rapid tyrosine phosphorylation of IRS1 and IRS2. This is a black box event because the kinase responsible for IRS phosphorylation is unclear.
R-HSA-8983011 (Reactome) Interleukin-7 (IL7) stimulation upregulates expression of the transcripts and proteins encoding Cytokine-inducible SH2-containing protein (CISH), Suppressor of cytokine signaling 1 (SOCS1) and Suppressor of cytokine signaling 2 (SOCS2) in CD8+ T cells (Ghazawi et al. 2016).
This is a black-box event since details of the mechanism of transcription and translation are omitted.
R-HSA-8983059 (Reactome) Inferred from mouse:
Following binding of TSLP to Cytokine receptor-like factor 2 (CRLF2, TSLPR) and Interleukin-7 receptor subunit alpha (IL7R), Signal transducer and activator of transcription 5A and 5B (STAT5A and STAT5B) and Signal transducer and activator of transcription 3 (STAT3) were phosphorylated in various Ba/F3 cell populations (Reche et al. 2001).
This is a black box event since the kinase responsible for STAT phosphorylation is unknown.
R-HSA-8983061 (Reactome) The functional receptor for human Thymic stromal lymphopoietin (TSLP) consists of two subunits, Cytokine receptor-like factor 2 (TSLPR) and Interleukin-7 receptor subunit alpha (IL7R) (Reche et al.2001).
This is a black box event since it is not clear whether this binding event occurs in association with other IL7 receptor complexes or independently.
R-HSA-8983063 (Reactome) Interleukin-7 (IL7) signaling is believed to resemble that of other gammaC family receptors, based on detailed studies of the Interleukin-2 receptor. Extending this model to IL7 suggested a series of events that bring Tyrosine-protein kinase JAK1 (JAK1) and Tyrosine-protein kinase JAK3 (JAK3) into proximity within the complex IL7:IL7R:JAK1:IL2RG:JAK3. Cytoplasmic domains of the receptor chains re-orient so that their associated kinases (JAKs and possibly phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). Tyrosine-449 (Y449) in the cytoplasmic domain of Interleukin-7 receptor is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999).
It has been sugggested that JAK1 phosphorylates IL7R (Jiang et al. 2004) and it is believed that JAK3, associated with IL2RG, phosphorylates the tyrosine residues in the cytoplasmic portion of IL7R that lead to recruitment of STATs (Fry & Mackall 2002). This is consistent with the lack of intrinsic tyrosine kinase activity in IL7R:JAK1 in the absence of IL2RG:JAK3 (Lai et al. 1996).
R-HSA-8983077 (Reactome) Inferred from mouse:

The receptor for Thymic stromal lymphopoietin (TSLP) consists of Cytokine receptor-like factor 2 (CRLF2, TSLPR) and Interleukin-7 receptor subunit alpha (IL7R). Ba/F3cells expressing human IL7R or human TSLPR, or both stimulated with TSLP induce phosphorylation of Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 5A or B (STAT5A, STAT5B or STAT5), only in cells expressing both receptors (Reche et al.2001).

This is a black box event since there is no experimental details confirming binding of STAT3 and STAT5 to the receptor complex.


R-HSA-8983078 (Reactome) Inferred from mouse:
Signal transducer and activator of transcription 5A, 5B (STAT5A and STAT5B) and Signal transducer and activator of transcription 3 (STAT3) are phosphorylated upon addition of human Thymic stromal lymphopoietin (TSLP) when both Cytokine receptor-like factor 2 (CRLF2) and Interleukin-7 Receptor (IL7R) are present (Reche et al. 2001). Subsequently the phosphorylated STATs dissociate.
This is black box event since as not been demonstrated experimentally.
R-HSA-9012671 (Reactome) Interleukin-7 (IL7) up-regulates Cytokine-inducible SH2-containing protein (CISH), Suppressor of cytokine signaling 1(SOCS1), Suppressor of cytokine signaling 2(SOCS2) and Suppressor of cytokine signaling 3 (SOCS3) mRNA transcripts in primary human CD8 T cells. IL7 induces CISH and SOCS1-3 transcripts via the JAK/STAT5 signaling pathway (Ghazawi et al. 2016).
Signal transducer and activator of transcription 5A (STAT5A) and Signal transducer and activator of transcription 5B (STAT5B) dimers bind to similar core gamma-interferon activated sequence (GAS) motifs (Soldaini et al., 2000). STAT5 also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. This is a black box event because apart of the mentioned here genes could be another subset of genes up or downregulated by STAT5. Genes that are regulated by STAT5 include Interleukin-2 receptor alpha (IL2RA) (John et al. 1996), TNFSF11 (RANKL), Connexin-26 (GJB2) and Cyclin D1 (Hennighausen & Robinson, 2005). A comprehensive listing of hepatic STAT5B regulated genes is available from microarray/STAT5B knockout mice (Clodfelter et al. 2006), and similarly for STAT5-dependent genes regulated by the GH receptor (Rowland et al. 2005, Barclay et al. 2011).
R-HSA-9025969 (Reactome) Signal transducer and activator of transcription 5A/B (STAT5A and/or STAT5B, typically referred to as STAT5) are believed to bind tyrosine-phosphorylated IL7R. Several studies have demonstrated STAT5 phosphorylation following Interleukin‑7 (IL7) ligand‑receptor interaction (Foxwell et al. 1995, van der Plas et al. 1996, Yu et al. 1998, Jufrroy et al. 2010, Landires et al. 2011).

STAT5 is activated in COS7 cells when co‑transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 is responsible for STAT5 phosphorylation in vivo (Lin & Leonard, 2000). STAT5 binding is represented here as a black box event as it is inferred to be a prerequisite of IL7-induced STAT5 phosphorylation.
RAG1:RAG2 recombinase:Immunoglobulin kappa locusArrowR-HSA-8865711 (Reactome)
RAG1:RAG2 recombinaseR-HSA-8865711 (Reactome)
SMARCA4R-HSA-8865605 (Reactome)
STAT3R-HSA-8983077 (Reactome)
STAT5A,STAT5BR-HSA-9025969 (Reactome)
TSLPR-HSA-8983061 (Reactome)
p-STAT3ArrowR-HSA-8983078 (Reactome)
p-STAT5 dimerArrowR-HSA-452102 (Reactome)
p-STAT5 dimerArrowR-HSA-507937 (Reactome)
p-STAT5 dimerR-HSA-507937 (Reactome)
p-STAT5 dimerR-HSA-8865626 (Reactome)
p-STAT5 dimerR-HSA-9012671 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-6785165 (Reactome)
p-STAT5A, p-STAT5BR-HSA-452102 (Reactome)
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