Interleukin-7 signaling (Homo sapiens)

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27414122512188, 117, 299, 17, 243419, 23281226122028222623, 282610221125, 226cytosolendoplasmic reticulum lumennucleoplasmCISH gene p-JAK3 AcK9,14,18-p-S10,T11-histone H3 JAK1 p-Y449-IL7R Immunoglobulin kappalocusp-STAT3 CISHPIK3R3 IL2RG PIK3C3 p-Y694-STAT5A PIK3R2 JAK1 LCK JAK3 SMARCA4 CISH ADPPIK3R1 SOCS2 IL2RG JAK1 JAK1 IL2RG CRLF2:IL7Rp-Y699-STAT5B IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:p-STAT5A,p-STAT5BBRWD1 gene p-Y694-STAT5A IL7R IL7 LCK HGF(495-728)PTK2B CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5Bp-Y449-IL7R IRS1 ADPTSLP ATPJAK1 LCK ATPADPATPPI(3,4,5)P3ATPIL7R ADPFYN IL7R IL7R ATPPIK3R2 SOCS2 gene AcK9,14-p-S10-histone H3 p-Y699-STAT5B JAK1 IL7 p-FYN IL7R TSLPPIK3C3,ATG14:PIK3C3:PIK3R4:p-S15-BECN1AcK9,14,18-p-S10,T11-histone H3 FYN IL7 p-FYN ELOC IL7 PIIL2RG:JAK3p-Y449-IL7R IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsp-PTK2B IL2RG STAT5B BRWD1 IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2p-Y694-STAT5A JAK3 Immunoglobulin kappa locus BRWD1 geneAcK9,14,18,79-p-S10,T11-histone H3 p-STAT5 dimerPI(4,5)P2AcK9,14-p-S10-histone H3 FYN FYN IL7R AcK14,18,79-p-S10-histone H3 LCK HGF(495-728):IL7CRLF2 STAT5B AcK14,18,79-p-T11-histone H3 PIK3CB IL7 IL7 p-FYN IL7:IL7R:JAK1:FYN:PTK2BADPPIK3R3 IL7R p-FYN ATPCISH gene, SOCS1gene, SOCS2gene:p-STAT5 dimerPIK3CA IL7R JAK1RAG1:RAG2recombinase:Immunoglobulin kappa locusPTK2B IRS1,IRS2p-S15-BECN1 IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3AcK14,18,79-p-T11-histone H3 p-STAT5A, p-STAT5Bp-JAK3 STAT5A LCK JAK1 SOCS2 IL7 AcK9,14-p-S10-HIST2H3A CISH gene, SOCS1gene, SOCS2 genePhospho-IRS1/2:PI3K(p85:p110)CISH CRLF2 IL7R:TSLP:CRLF2:p-STAT3BRWD1 AcK14,18-p-T11-histone H3 PIK3R4 IL7STAT3JAK1 AcK14,18,79-p-S10,T11-histone H3 IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BIL7 IL7R:TSLP:CRLF2p-Y694-STAT5A p-FYN IL7 BRWD1 IL7 ADPIL7 p-JAK3 STAT5A IL7 STAT5A,STAT5BRAG1 IL2RG IL7R CRLF2 JAK3 RAG2 ELOC:CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BIL7RADPSOCS1 AcK14,18,79-p-S10,T11-histone H3 SOCS1 gene SOCS1 gene RAG1 PIP3 activates AKTsignalingp-Y449-IL7R p-Y449-IL7R p-Y694-STAT5A p-FYN p-FYN JAK1 FYN IL7R:FYN:LCKRAG2 AcK14,18-p-S10-histone H3 AcK14,18,79-p-S10-histone H3 AcK14,18-p-S10-histone H3 p-Y699-STAT5B IL2RGPIK3R2 p-Y-IRS1 IL2RG IL2RG AcK14,18-p-T11-histone H3 p-Y699-STAT5B JAK1 IL7:IL7R:JAK1:p-PTK2BIL7 p-JAK3 SOCS2 IL7:IL7R:JAK1:FYN:p-LCKp-Y694-STAT5A BRWD1:AcK9,14-pS10-histone H3IL7R:TSLP:CRLF2:STAT3CISH ELOCATPJAK3 IL7R STAT5B AcK14,18-p-S10,T11-histone H3 FYNATPCISH gene BRWD1FYN IRS1 IL7:IL7R:JAK1:FYN:LCKp-Y449-IL7R HGF(495-728) FYN BRWD1:AcK(9,14,18,79)-p(S10,T11)-histone H3JAK3 JAK1 IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3PIK3R1 p-STAT5 dimerp-Y699-STAT5B RAG1:RAG2recombinaseSTAT5A p-LCK LCK p-Y-IRS2 JAK1 TSLP IL2RG p-Y449-IL7R IL7R IL7:IL7R:JAK1:p-FYNPIK3R2 BRWD1:SMARCA4CRLF2 SOCS2PIK3R1 p-FYN p-STAT3TSLP STAT5B PI3Pp-Y699-STAT5B IL7 JAK1 STAT5A IRS2 IL2RG AcK9,14-p-S10-HIST1H3A IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3ADPp-FYN JAK3IL7R IL7R:LCK:FYN:JAK1CISH,SOCS1,SOCS2JAK3 JAK1 AcK(9,14,18,79)-p(S10,T11)-histone H3IL7 JAK1 LCKSTAT3 JAK1 AcK14,18-p-S10,T11-histone H3 SMARCA4p-Y449-IL7R p-FYN PI3K regulatorysubunitsIRS2 ADPPIK3R1 SOCS2 gene AcK9,14,18,79-p-S10,T11-histone H3 2x(p-STAT5A,p-STAT5B):BRWD1 geneIL7R:JAK1:FYN:PTK2BIL2RG ATPPIK3R3 IL7R ATG14 522513, 1555265555522516526544521165513, 156215126165231216251212526


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: 62
Reactome Author 
Reactome Author: Ray, KP

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Bibliography

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  1. Yu CR, Young HA, Ortaldo JR.; ''Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells.''; PubMed Europe PMC Scholia
  2. 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 Scholia
  3. 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 Scholia
  4. 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 Scholia
  5. 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 Scholia
  6. 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 Scholia
  7. 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 Scholia
  8. 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 Scholia
  9. 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 Scholia
  10. 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 Scholia
  11. 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 Scholia
  12. Huang H, Rambaldi I, Daniels E, Featherstone M.; ''Expression of the Wdr9 gene and protein products during mouse development.''; PubMed Europe PMC Scholia
  13. 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 Scholia
  14. 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 Scholia
  15. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC Scholia
  16. 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 Scholia
  17. 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 Scholia
  18. 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 Scholia
  19. 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 Scholia
  20. 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 Scholia
  21. 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 Scholia
  22. 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 Scholia
  23. 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 Scholia
  24. 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 Scholia
  25. 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 Scholia
  26. 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 Scholia
  27. 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 Scholia

History

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CompareRevisionActionTimeUserComment
112492view15:45, 9 October 2020ReactomeTeamReactome version 73
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)
ATG14 ProteinQ6ZNE5 (Uniprot-TrEMBL)
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)
CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BComplexR-HSA-8982973 (Reactome)
CISHProteinQ9NSE2 (Uniprot-TrEMBL)
CRLF2 ProteinQ9HC73 (Uniprot-TrEMBL)
CRLF2:IL7RComplexR-HSA-8982873 (Reactome)
ELOC ProteinQ15369 (Uniprot-TrEMBL)
ELOC:CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BComplexR-HSA-8982996 (Reactome)
ELOCProteinQ15369 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
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:FYN:LCKComplexR-HSA-449983 (Reactome)
IL7:IL7R:JAK1:FYN:PTK2BComplexR-HSA-8982920 (Reactome)
IL7:IL7R:JAK1:FYN:p-LCKComplexR-HSA-8982933 (Reactome)
IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3ComplexR-HSA-449967 (Reactome)
IL7:IL7R:JAK1:p-FYNComplexR-HSA-8982908 (Reactome)
IL7:IL7R:JAK1:p-PTK2BComplexR-HSA-8982932 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2ComplexR-HSA-8982992 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:PI3K-regulatory subunitsComplexR-HSA-1295544 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3ComplexR-HSA-1295546 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BComplexR-HSA-6785159 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:p-STAT5A,p-STAT5BComplexR-HSA-8982988 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3ComplexR-HSA-8982909 (Reactome)
IL7ProteinP13232 (Uniprot-TrEMBL)
IL7R ProteinP16871 (Uniprot-TrEMBL)
IL7R:FYN:LCKComplexR-HSA-8982907 (Reactome)
IL7R:JAK1:FYN:PTK2BComplexR-HSA-8982922 (Reactome)
IL7R:LCK:FYN: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. More family members are to be confirmed and added in the future.
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)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCKProteinP06239 (Uniprot-TrEMBL)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
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.
PI3PMetaboliteCHEBI:26034 (ChEBI)
PIMetaboliteCHEBI:16749 (ChEBI)
PIK3C3 ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3C3,ATG14:PIK3C3:PIK3R4:p-S15-BECN1ComplexR-HSA-9015652 (Reactome) Mice with T-cell-restricted Vps34 deficiency have decreased T cell numbers in the thymus and peryphery. Altough Vps34 associated lymphopenia is not related to a defect in autophagy, Vps34 deficient naive T cells have decreased cell surface expression of CD127, despite normal total levels of CD127(22551764, )
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIK3R4 ProteinQ99570 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PTK2B ProteinQ14289 (Uniprot-TrEMBL)
Phospho-IRS1/2:PI3K(p85:p110)ComplexR-HSA-198344 (Reactome)
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)
SOCS2ProteinO14508 (Uniprot-TrEMBL)
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-FYN ProteinP06241 (Uniprot-TrEMBL)
p-JAK3 ProteinP52333 (Uniprot-TrEMBL)
p-LCK ProteinP06239 (Uniprot-TrEMBL)
p-PTK2B ProteinQ14289 (Uniprot-TrEMBL)
p-S15-BECN1 ProteinQ14457 (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-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
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-198266 (Reactome)
ADPArrowR-HSA-8983022 (Reactome)
ADPArrowR-HSA-8983059 (Reactome)
ADPArrowR-HSA-8983063 (Reactome)
ADPArrowR-HSA-8983071 (Reactome)
ADPArrowR-HSA-8983080 (Reactome)
ADPArrowR-HSA-9015643 (Reactome)
ATPR-HSA-1295519 (Reactome)
ATPR-HSA-1295540 (Reactome)
ATPR-HSA-198266 (Reactome)
ATPR-HSA-8983022 (Reactome)
ATPR-HSA-8983059 (Reactome)
ATPR-HSA-8983063 (Reactome)
ATPR-HSA-8983071 (Reactome)
ATPR-HSA-8983080 (Reactome)
ATPR-HSA-9015643 (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)
CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BArrowR-HSA-8983008 (Reactome)
CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BR-HSA-8983007 (Reactome)
CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BTBarR-HSA-6785165 (Reactome)
CISHR-HSA-8983008 (Reactome)
CRLF2:IL7RR-HSA-8983061 (Reactome)
ELOC:CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BArrowR-HSA-8983007 (Reactome)
ELOC:CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BR-HSA-8983020 (Reactome)
ELOCR-HSA-8983007 (Reactome)
FYNR-HSA-8983012 (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:FYN:LCKArrowR-HSA-449978 (Reactome)
IL7:IL7R:JAK1:FYN:LCKR-HSA-8983022 (Reactome)
IL7:IL7R:JAK1:FYN:LCKR-HSA-8983071 (Reactome)
IL7:IL7R:JAK1:FYN:LCKmim-catalysisR-HSA-8983071 (Reactome)
IL7:IL7R:JAK1:FYN:PTK2BArrowR-HSA-8983021 (Reactome)
IL7:IL7R:JAK1:FYN:PTK2BR-HSA-8983080 (Reactome)
IL7:IL7R:JAK1:FYN:PTK2Bmim-catalysisR-HSA-8983080 (Reactome)
IL7:IL7R:JAK1:FYN:p-LCKArrowR-HSA-8983071 (Reactome)
IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3ArrowR-HSA-449958 (Reactome)
IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3R-HSA-1295519 (Reactome)
IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3mim-catalysisR-HSA-1295519 (Reactome)
IL7:IL7R:JAK1:p-FYNArrowR-HSA-8983022 (Reactome)
IL7:IL7R:JAK1:p-FYNR-HSA-449958 (Reactome)
IL7:IL7R:JAK1:p-PTK2BArrowR-HSA-8983080 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits:IRS1,IRS2ArrowR-HSA-8983003 (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)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3ArrowR-HSA-1295519 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3R-HSA-1295516 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3R-HSA-8983063 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3mim-catalysisR-HSA-8983063 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BArrowR-HSA-6785165 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BR-HSA-8983008 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5Bmim-catalysisR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:p-STAT5A,p-STAT5BArrowR-HSA-1295540 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:p-STAT5A,p-STAT5BR-HSA-8983005 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3ArrowR-HSA-8983005 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3ArrowR-HSA-8983063 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3R-HSA-6785165 (Reactome)
IL7R-HSA-1266684 (Reactome)
IL7R-HSA-449978 (Reactome)
IL7R-HSA-8983021 (Reactome)
IL7R:FYN:LCKArrowR-HSA-8983012 (Reactome)
IL7R:FYN:LCKR-HSA-1264832 (Reactome)
IL7R:JAK1:FYN:PTK2BR-HSA-8983021 (Reactome)
IL7R:LCK:FYN:JAK1ArrowR-HSA-1264832 (Reactome)
IL7R:LCK:FYN: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-8983012 (Reactome)
IRS1,IRS2R-HSA-8983003 (Reactome)
Immunoglobulin kappa locusR-HSA-8865711 (Reactome)
JAK1R-HSA-1264832 (Reactome)
JAK3R-HSA-451895 (Reactome)
LCKR-HSA-8983012 (Reactome)
PI(3,4,5)P3ArrowR-HSA-198266 (Reactome)
PI(4,5)P2R-HSA-198266 (Reactome)
PI3K regulatory subunitsR-HSA-1295516 (Reactome)
PI3PArrowR-HSA-9015643 (Reactome)
PIK3C3,ATG14:PIK3C3:PIK3R4:p-S15-BECN1mim-catalysisR-HSA-9015643 (Reactome)
PIR-HSA-9015643 (Reactome)
Phospho-IRS1/2:PI3K(p85:p110)mim-catalysisR-HSA-198266 (Reactome)
R-HSA-1264832 (Reactome) Interleukin-7 receptor (IL7R) has the small juxta-membrane Box1 motif, conserved throughout the type 1 cytokine receptor family (Murakami et al. 1991). This is believed to be the site of JAK1 binding (Tanner et al. 1995); deletion of Box1 eliminates JAK1 phosphorylation (Jiang et al. 2004). Studies with T-cell lines expressing mutant Interleukin-4/Interleukin-7 chimeric receptors revealed that loss of Box1 results 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). Tyrosine-protein kinase Fyn (FYN) associates to the receptor IL7R constitutively (Seckinger & Fougereau 1994; Venkitaraman & Cowling 1992).
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) Multiple observations support a role for Interleukin-7-stimulated JAK/STAT signaling. Interleukin-7 (IL7) induces rapid and dose-dependent tyrosine phosphorylation of Tyrosine-protein kinase JAK1 (JAK1) and Tyrosine-protein kinase JAK3 (JAK3), with concomitant tyrosine phosphorylation and DNA-binding activity of Signal transducer and activator of transcription 5A or 5B (STAT5A or STAT5B, or to simplify: STAT5) (Foxwell et al. 1995). Interleukin-7 receptor subunit alpha (IL7R) was shown to directly induce the activation of JAKs and Signal transducer and activator of transcription 1-alpha/beta (STAT1), STAT5A or STAT5B, and Signal transducer and activator of transcription 3 (STAT3) by van der Plas et al. (1996). In primary human T cells and NK cells, IL7 induced activation of STAT5A, STAT5B and to a lesser extent STAT1 and STAT3 (Yu et al. 1998). JAK1 and JAK3 knockout mice displayed severely impaired thymic development, suggesting that both are involved in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995). STAT5 are activated in COS 7 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); it is not clear which kinase phosphorylates STAT5 in vivo. Furthermore STAT5 can be phosphorylated after Thymic stromal lymphopoietin (TLSP) stimulation.
TSLP induces phosphorylation of STAT3 and STAT5. Phosphorylation of STAT5 and STAT3 by human TSLP has been only detected on cells expressing both receptors IL7R and Cytokine receptor-like factor 2(TSLPR) (Reche et al.2001).
R-HSA-198266 (Reactome) PI3-kinase phosphorylates several phosphatidyl-inositides (phospholipids) at the plasma membrane: the most relevant is PtdIns(3,4,5)P3, also named PIP3.
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). The membrane-associated IL2RG chain 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.
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 Interleukin receptor common gamma chain (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 Interleukin-2 Receptor Gamma (IL2RG) in the final complex (McElroy et al. 2007).
R-HSA-451895 (Reactome) Cytokine receptor common subunit gamma (IL2RG), also termed IL-2 receptor gamma chain, associates with Tyrosine-protein kinase JAK3 (JAK3) (Hofmann et al. 2004). The carboxyl terminal region of IL2RG has been shown to be important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994).
R-HSA-452102 (Reactome) The Signal transducer and activator of transcription 5A(STAT5A) and Signal transducer and activator of transcription 5B(STAT5B) forms are encoded by 2 closely-related genes. They are thought to be present largely as monomers in unstimulated cells but rapidly form homo- and hetero-dimers upon stimulation (Cella et al. 1998). Tyrosine phosphorylation of STAT monomers allows dimers to form through reciprocal phosphotyrosine-SH2 interactions. The dimers translocate to the nucleus and bind to STAT-specific DNA-response elements of target genes to induce gene transcription (Baker et al.2007). STAT5A/B homo- and hetero-tetramers have also been shown to occur downstream of Interleukin-2 (IL2) and may have a distinct or expanded target repertoire from STAT5A/B dimers. Although STAT5 andA STAT5B are highly homologous at the DNA and protein levels, each has unique functions, as demonstrated by studies comparing mice lacking one isoform or the other. However, it is also known that STAT5A and STAT5B share a number of functions and that the phenotype of mice lacking both STAT5A and STAT5B is more severe than those lacking either one individually, which suggest that there may be some redundancy or that they cooperate in order to achieve the full spectrum of STAT5-dependent activities (Moriggl et al. 1999, Teglund et al. 1998).
R-HSA-507937 (Reactome) 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). STAT5A/B also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. 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-6785165 (Reactome) Inferred from mouse: Tyrosine-449 (Y449) in the cytoplasmic domain of Interleukin-7 receptor alpha subunit (IL7R) 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 is thought that phosphorylated Y449 is a docking site for STAT5 (Pallard et al. 1999). T-cells from an IL7R Y449F knock-in mouse did not activate Signal transducer and activator of transcription 5 (STAT5A or STAT5B) (Osbourne et al. 2007), indicating that Y449 is a key residue regulating Interleukin-7-mediated STAT5 activation.
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-8983005 (Reactome) Inferred from mouse: Interleukin-7(IL7) induces activation of JAK1, JAK3 and various STAT5 isoforms and concomitant double stranded DNA binding activity of STAT5 A/B. Induction of JAK/STAT pathway shows a very close correlation with IL7-induced growth of CT6 cells. These results demonstrate that the Jak/STAT system is utilized by IL7, and that this signaling mechanism is likely to be involved in the growth promoting properties of the cytokine (Foxwell et al.1995). This is black box event since there is not detail about how this dissociation occurs.
R-HSA-8983007 (Reactome) Suppressor of cytokine signaling proteins ( CISH and SOCS2) bind directly to Elongin C (ELOC) via their SOCS box, thereby recruiting the multi-protein E3 ubiquitin-ligase complex, which results in the ubiquitination and subsequent proteosomal degradation of associated receptors (Ghazawi et al. 2016).

This is a black box event since there are no details about the order of the steps and when exactly this event occurs.


R-HSA-8983008 (Reactome) Suppressor of cytokine signaling 1 (SOCS1) and Cytokine-inducible SH2-containing protein (CISH, CIS) bind the activated Interleukin-7 receptor complex (Ghazawi et al. 2016).

This is a black box event since the order of complex formation 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-8983012 (Reactome) The Interleukin-7R (IL7R) in both unstimulated and activated human Tcells is physically associated with two molecules with intrinsic kinase activity. Western blotting analysis reveals these proteins to be the src kinase enzymes, Tyrosine-protein kinase Fyn(FYN) and Tyrosine-protein kinase Lck(LCK) (Page et al.1995).

This is a black box event since there is no evidence about the subcellular compartment where this association.


R-HSA-8983020 (Reactome) Following IL7 stimulation, Interleukin-7 receptor subunit alpha (IL7R) is internalized and degraded. Interleukin-7 (IL7) induces the expression of Suppressor of cytokine signaling (SOCS) proteins Cytokine-inducible SH2-containing protein (CISH, CIS), Suppressor of cytokine signaling 1 (SOCS1) and Suppressor of cytokine signaling 2 (SOCS2) through the JAK/STAT5 pathway. CISH and SOCS2 specifically interact with IL7R in early endosomes, directing the receptor complex to the proteasome for degradation (Ghazawi et al. 2016). This is a black-box event since details of the translocation and degradation are omitted.
R-HSA-8983021 (Reactome) Interleukin-7 (IL7) binds Interleukin-7 receptor alpha chain (IL7R). Protein-tyrosine kinase 2-beta (PTK2B, PYK2) physically associates with Tyrosine-protein kinase JAK1 prior to IL7 stimulation and increases its association with IL7R following IL7 stimulation (Benbernou et al. 2000).
This is a black box event since Protein-tyrosine kinase 2-beta (PTK2B or PYK2) may bind indirectly to the receptor complex via other cytosolic proteins. Here it is represented as an independent binding event.
R-HSA-8983022 (Reactome) Following IL7 stimulation, Interleukin-7 receptor alpha (IL7R) associated protein, tyrosine-protein kinase Fyn (FYN) is autophosphorylated
(Seckinger & Fougereau 1994).

This is a black box event because the catalyst of FYN phosphorylation and the significance of this event are unclear.


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) The membrane-proximal part of the intracellular domain of the Interleukin-7 receptor subunit alpha (IL7R) plays a critical role in the association with JAKs. Both IL7 and IL2 receptor complexes contain a common IL2RG receptor subunit chain. In the IL2 receptor complex, pre-association of Tyrosine-protein kinase JAK1 (JAK1) with the Cytokine receptor subunit beta (IL2RB) chain and Tyrosine-protein kinase JAK3 (JAK3) with the gamma (IL2RG) chain has been shown ( Lin et al. 1995).

Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3. Jak1 and Jak3 were found to be selectively associated with the "serine-rich" region of IL-2R beta and the carboxyl-terminal region of IL-2R gamma (Miyazaki et al.1994)


This is a black box event since there are no details about the phosphorylated regions.
R-HSA-8983071 (Reactome) The Interleukin-7 receptor subunit alpha/Tyrosine-protein kinase Lck (IL7R:LCK) complex phosphorylates LCK after Interleukin-7 (IL7) activation. IL7R immunoprecipitates from both resting and activated PBMCs, purified mature Tcells and unfractionated thymocytes all contained the Src family tyrosine-protein kinases FYN and LCK . IL7 enhanced FYN and LCK auto-phosphorylation and their ability to phosphorylate an exogenously added substrate in both resting (t =0) and activated (t = 48h) PBMCs (Page et al. 1995).
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-8983080 (Reactome) Inferred from mouse: Protein-tyrosine kinase 2-beta (PTK2B, PYK2) may be phosphorylated by Tyrosine-protein kinase JAK1 rather than JAK3, as JAK1 and PTK2B can physically associate. Basal phosphorylation of PTK2B in the absence of Interleukin-7 (IL7) may be due to a different kinase (Benbernou et al.2000). PYK2 was found to physically associate with JAK1 prior to IL7 stimulation and increased its association with Interleukin-7 receptor alpha subunit (IL7RA) following IL7 stimulation. Stimulation of D1 (or normal pro-T) cells by IL7 rapidly increased tyrosine phosphorylation and enzymatic activity of PTK2B, with kinetics slightly lagging that of JAK1 and JAK3 phosphorylation (Benbernou et al. 2000).

This is a BlackBox event as the kinase that phosphorylates PTK2B is unknown.
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).
R-HSA-9015643 (Reactome) The Beclin-1 complex (ATG14:PIK3C3:PIK3R4:BECN1) is essential for autophagosome formation (Matsunaga et al. 2009, 2010). PIK3C3 (VPS34), the catalytic component of this complex, is a class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) producing phosphatidylinositol 3-phosphate (PI3P). PIK3C3 is essential for the early stages of autophagy and colocalizes strongly with early autophagosome markers (Axe et al. 2008). The role of PI3P in autophagosome formation is to recruit WIPI2b (Dooley et al. 2014) a member of the WIPI family (Proikas-Cezanne et al. 2004, 2015, Polson et al. 2010).
RAG1:RAG2 recombinase:Immunoglobulin kappa locusArrowR-HSA-8865711 (Reactome)
RAG1:RAG2 recombinaseR-HSA-8865711 (Reactome)
SMARCA4R-HSA-8865605 (Reactome)
SOCS2R-HSA-8983008 (Reactome)
STAT3R-HSA-8983077 (Reactome)
STAT5A,STAT5BR-HSA-6785165 (Reactome)
TSLPR-HSA-8983061 (Reactome)
mim-catalysisR-HSA-1295540 (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-8983005 (Reactome)
p-STAT5A, p-STAT5BR-HSA-452102 (Reactome)
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