Interleukin-7 signaling (Homo sapiens)

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6, 141821737125, 8, 91015, 1610, 194nucleoplasmcytosolIL7 IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3p-FYN IL7 HGF(495-728) AcK14,18-p-S10,T11-histone H3 IL7R:LCK:FYN:JAK1JAK3 PIK3R2 IL2RG:JAK3AcK9,14-p-S10-histone H3 IL7:IL7R:JAK1:FYN:LCKJAK1 Immunoglobulin kappa locus IL2RG JAK3IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:p-STAT5A,p-STAT5BPI(3,4,5)P3p-JAK3 p-Y694-STAT5A JAK1 JAK1 IL7 IL7R AcK9,14,18-p-S10,T11-histone H3 p-FYN JAK3 p-STAT5 dimerIL7R IL7R BRWD1 BRWD1 BRWD1 geneBRWD1:AcK(9,14,18,79)-p(S10,T11)-histone H3PIK3R2 FYN LCK RAG2 PIK3R1 p-Y449-IL7R IL7 RAG1:RAG2recombinaseIL2RG p-FYN SMARCA4 IL7:IL7R:JAK1:p-FYN:IL2RG:JAK3p-JAK3 2x(p-STAT5A,p-STAT5B):BRWD1 geneJAK1 AcK14,18-p-S10-histone H3 IL2RG CISH RAG1:RAG2recombinase:Immunoglobulin kappa locusTSLP p-Y449-IL7R p-Y694-STAT5A HGF(495-728)IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3JAK1 IL7R IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3:STAT5A,STAT5BSTAT5B HGF(495-728):IL7IL2RG Phospho-IRS1/2:PI3K(p85:p110)IL2RG IL7 PI3K regulatorysubunitsIL7 PIP3 activates AKTsignalingIL7 JAK1 p-Y699-STAT5B AcK9,14-p-S10-HIST2H3A JAK1 p-JAK3 ADPAcK9,14,18,79-p-S10,T11-histone H3 p-JAK3 AcK14,18-p-T11-histone H3 PIK3R3 p-Y699-STAT5B BRWD1:AcK9,14-pS10-histone H3IL2RG LCK IL2RG p-Y449-IL7R JAK1 p-FYN p-STAT5A, p-STAT5BIL2RGp-FYN AcK14,18-p-T11-histone H3 PIK3R1 IL7PIK3R2 JAK1 STAT5B JAK1 IL7 IL7R:FYN:LCKATPLCK ADPAcK14,18,79-p-S10-histone H3 AcK14,18,79-p-S10-histone H3 AcK14,18-p-S10,T11-histone H3 PI(4,5)P2AcK14,18,79-p-S10,T11-histone H3 p-Y449-IL7R STAT5A FYN Immunoglobulin kappalocusAcK9,14-p-S10-histone H3 PIK3R3 CRLF2 p-Y694-STAT5A STAT5A CISH:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5Bp-STAT5 dimerPIK3CA IL7 AcK9,14,18,79-p-S10,T11-histone H3 PIK3CB PIK3R1 p-Y699-STAT5B IL7R IL2RG p-JAK3 BRWD1:SMARCA4p-JAK3 p-Y694-STAT5A BRWD1p-FYN IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunitsSTAT5A STAT5B p-Y699-STAT5B AcK14,18,79-p-T11-histone H3 SMARCA4JAK1BRWD1 AcK9,14,18-p-S10,T11-histone H3 ATPAcK14,18-p-S10-histone H3 RAG1 IL7:IL7R:JAK1:p-FYNAcK14,18,79-p-T11-histone H3 BRWD1 gene ADPSTAT5A,STAT5BIL7 p-Y-IRS2 p-Y699-STAT5B p-FYN IL7R ATPAcK(9,14,18,79)-p(S10,T11)-histone H3AcK14,18,79-p-S10,T11-histone H3 RAG2 SOCS2 AcK9,14-p-S10-HIST1H3A p-Y449-IL7R IL7R:TSLP:CRLF2p-FYN p-Y-IRS1 FYN p-Y449-IL7R p-Y694-STAT5A RAG1 201019191119191911191119119101213191911191119191919201919211119


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: 61
Reactome Author 
Reactome Author: Ray, KP

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Bibliography

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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:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BComplexR-HSA-8982973 (Reactome)
CRLF2 ProteinQ9HC73 (Uniprot-TrEMBL)
FYN ProteinP06241 (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:p-FYN:IL2RG:JAK3ComplexR-HSA-449967 (Reactome)
IL7:IL7R:JAK1:p-FYNComplexR-HSA-8982908 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunitsComplexR-HSA-1295544 (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-1295546 (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:LCK:FYN:JAK1ComplexR-HSA-1264843 (Reactome)
IL7R:TSLP:CRLF2ComplexR-HSA-8982872 (Reactome)
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)
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.
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (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.
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)
SOCS2 ProteinO14508 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5A,STAT5BComplexR-HSA-452094 (Reactome)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
TSLP ProteinQ969D9 (Uniprot-TrEMBL)
p-FYN ProteinP06241 (Uniprot-TrEMBL)
p-JAK3 ProteinP52333 (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)
ATPR-HSA-1295519 (Reactome)
ATPR-HSA-1295540 (Reactome)
ATPR-HSA-198266 (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:SOCS2:IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:JAK3:STAT5A,STAT5BTBarR-HSA-6785165 (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: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-FYNR-HSA-449958 (Reactome)
IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunitsArrowR-HSA-1295516 (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,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-JAK3ArrowR-HSA-1295519 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3R-HSA-1295516 (Reactome)
IL7:p-Y449-IL7R:JAK1:p-FYN:IL2RG:p-JAK3R-HSA-6785165 (Reactome)
IL7R-HSA-1266684 (Reactome)
IL7R-HSA-449978 (Reactome)
IL7R:FYN:LCKR-HSA-1264832 (Reactome)
IL7R:LCK:FYN:JAK1ArrowR-HSA-1264832 (Reactome)
IL7R:LCK:FYN:JAK1R-HSA-449978 (Reactome)
Immunoglobulin kappa locusR-HSA-8865711 (Reactome)
JAK1R-HSA-1264832 (Reactome)
JAK3R-HSA-451895 (Reactome)
PI(3,4,5)P3ArrowR-HSA-198266 (Reactome)
PI(4,5)P2R-HSA-198266 (Reactome)
PI3K regulatory subunitsR-HSA-1295516 (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 constituvely (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) The p85 subunit of PI3-kinase (PI3K) binds to phosphorylated Tyrosine-449 (Y449) on Interleukin-7 receptor subunit alpha (IL7R or IL7RA). Y449F substitution inhibits PI3K-dependent proliferation of Interleukin-7(IL7)-stimulated murine B-lineage cells (Venkitaraman & Cowling 1994). Stimulation of human lymphocyte precursor cells with IL7 induced tyrosine phosphorylation of the Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1 or p85 subunit of PI3K) and activation of its 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(RAC-alpha/beta/gamma serine/threonine-protein kinase), 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) suggest 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 iinhibiting the expression of pro-apoptotic factors BAX and BAD.
Interleukin-7 induced PI3K-dependent phosphorylation of AKT1 (Akt1 or PKB) and its downstream targets ,Glycogen synthase kinase-3 alpha/beta (GSK3A/B) Forkhead box protein O1 (FOXO1), and Forkhead box protein O3 (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 suggests 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 imvolved 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) IL-2 receptor gamma chain (IL2RG) associates with Tyrosine-protein kinase JAK3 (JAK3). 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.
RAG1:RAG2 recombinase:Immunoglobulin kappa locusArrowR-HSA-8865711 (Reactome)
RAG1:RAG2 recombinaseR-HSA-8865711 (Reactome)
SMARCA4R-HSA-8865605 (Reactome)
STAT5A,STAT5BR-HSA-6785165 (Reactome)
mim-catalysisR-HSA-1295540 (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-STAT5A, p-STAT5BR-HSA-452102 (Reactome)
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