Jak/STAT Signaling Pathway

Click on one of the cytokine subfamilies or receptor type to see the specific Jak and STAT molecules activated by members of the family.

IFN-alpha/beta
IFN-alpha/beta
IFN-alpha/
beta R
IFN-alpha/
beta R
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Tyk2
Tyk2
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Jak1
Jak2
Jak1
Jak2
STAT1
STAT2
STAT3
STAT4
STAT5
STAT6
STAT1
STAT2
STAT3
STAT4
STAT5
STAT6
STAT
Dimer
STAT
Dimer
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IRF9
IRF9
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STAT Dimer
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IRF9
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IFN-gamma
IFN-gamma
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IFN-
gamma R
IFN-
gamma R
Jak1
Jak2
Tyk2
Jak1
Jak2
Tyk2
STAT1
STAT2
STAT3
STAT5
STAT6
STAT1
STAT2
STAT3
STAT5
STAT6
STAT
Dimer
STAT Dimer
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EGF
EGF
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EGF R/
ErbB1
EGF R/
ErbB1
Src
Src
Jak1
Jak2
Jak1
Jak2
STAT1
STAT3
STAT5
STAT1
STAT3
STAT5
STAT
Dimer
STAT Dimer
Erythropoietin
Erythropoietin
Erythropoietin R
Erythropoietin R
Jak2
Jak3
Jak2
Jak3
STAT1
STAT3
STAT5
STAT1
STAT3
STAT5
STAT
Dimer
STAT Dimer
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IL-6
IL-6
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IL-6 R
IL-6 R
Jak1
Jak2
Tyk2
Jak1
Jak2
Tyk2
STAT1
STAT3
STAT1
STAT3
STAT
Dimer
STAT Dimer
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IL-2
IL-2
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IL-2 R
IL-2 R
Jak1
Jak2
Jak3
Jak1
Jak2
Jak3
STAT1
STAT3
STAT4
STAT5
STAT6
STAT1
STAT3
STAT4
STAT5
STAT6
STAT
Dimer
STAT Dimer
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IL-3
IL-3
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IL-3 R
IL-3 R
Src
Src
Jak1
Jak2
Tyk2
Jak1
Jak2
Tyk2
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STAT3
STAT3
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STAT1
STAT3
STAT5
STAT6
STAT1
STAT3
STAT5
STAT6
STAT
Dimer
STAT Dimer
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IL-10
IL-10
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IL-10 R
IL-10 R
Jak1
Jak2
Tyk2
Jak1
Jak2
Tyk2
STAT1
STAT3
STAT5
STAT1
STAT3
STAT5
STAT
Dimer
STAT Dimer
IL-12
IL-12
IL-12 R
IL-12 R
Jak2
Tyk2
Jak2
Tyk2
STAT1
STAT3
STAT4
STAT5
STAT6
STAT1
STAT3
STAT4
STAT5
STAT6
STAT
Dimer
STAT Dimer
Angiotensin II
Angiotensin II
AGTR-1
AGTR-1
G Protein
G Protein
PLC-beta
PLC-beta
PIP2
PIP2
IP3
IP3
DAG
DAG
Ca2+
Ca2+
PKC
delta
PKC
delta
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PYK2
PYK2
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Jak2
Jak2
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SHP-2
SHP-2
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Jak1
Jak2
Tyk2
Jak1
Jak2
Tyk2
STAT1
STAT2
STAT3
STAT5
STAT6
STAT1
STAT2
STAT3
STAT5
STAT6
STAT
Dimer
STAT Dimer
CXCL12/
SDF-1
alpha
CXCL12/
SDF-1
alpha
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CXCR4
CXCR4
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Jak1
Jak2
Jak3
Tyk2
Jak1
Jak2
Jak3
Tyk2
STAT1
STAT2
STAT3
STAT4
STAT5
STAT1
STAT2
STAT3
STAT4
STAT5
STAT
Dimer
STAT Dimer
STAT Dimer
ISRE
Anti-viral
GAS
Type I-II Interferons
Ligand Receptor Complex Activated Jak Activated STAT
IFN-alpha IFN-alpha-beta R1 +  Jak1 STAT1
IFN-alpha-beta R2 Jak2 STAT2
  Tyk2 STAT3
    STAT4
    STAT5
      STAT6
IFN-beta IFN-alpha-beta R1 +  Jak1 STAT1
IFN-alpha-beta R2 Jak2 STAT2
  Tyk2 STAT3
    STAT4
    STAT5
      STAT6
IFN-gamma IFN-gamma R1-CD119 +  Jak1 STAT1
IFN-gamma R2 Jak2 STAT2
  Tyk2 STAT3
    STAT5
    STAT6
Cell Migration
Receptor Tyrosine Kinases
Ligand Receptor Complex Activated Jak Activated STAT
Angiopoietin-2 Tie-2   STAT3
      STAT5
BDNF TrkB Jak2 STAT1
      STAT3
EGF EGF R/ErbB1 Jak1 STAT1
  Jak2 STAT3
      STAT5
EGF ErbB2/Her2 Jak2 STAT1
    STAT3
      STAT5
EGF ErbB4/Her4 Jak2 STAT1
      STAT5
Ephrin-A EphA4 Jak2 STAT1
      STAT3
FGF FGF R1 Jak1 STAT1
FGF R2 Jak2 STAT3
FGF R3 Jak3 STAT5
  FGF R4 Tyk2  
Gas6 Mer   STAT3
    STAT5
      STAT6
HGF HGF R/c-MET Jak1 STAT1
  Jak2 STAT3
      STAT5
IGF-I IGF-I R Jak1 STAT3
    Jak2 STAT5
M-CSF M-CSF R Jak1 STAT1
  Tyk2 STAT3
      STAT5
PBEF/Visfatin Insulin R/CD220 Jak2 STAT3
PDGF PDGF R alpha Jak1 STAT1
PDGF R beta Jak2 STAT3
  Tyk2 STAT5
      STAT6
SCF/c-kit Ligand SCF R/c-kit Jak2 STAT1
    STAT3
      STAT5
VEGF VEGF R1/Flt-1 Jak2 STAT1
VEGF R2/KDR/Flk-1 Tyk2 STAT3
VEGF R3/Flt-4   STAT5
      STAT6
Hematopoietic Cell
Differentiation and Proliferation
Homodimeric Hormone Receptors
Ligand Receptor Complex Activated Jak Activated STAT
Erythropoietin Erythropoietin R Jak2 STAT1
  Jak3 STAT3
      STAT5
Growth Hormone Growth Hormone R Jak1 STAT1
  Jak2 STAT3
      STAT5
Prolactin Prolactin R Jak1 STAT1
  Jak2 STAT3
      STAT5
Thrombopoietin/Tpo Thrombopoietin R/Tpo R Jak2 STAT1
  Tyk2 STAT3
      STAT5
Immune Cell Differentiation
Inflammation
Il-6 Family
Ligand Receptor Complex Activated Jak Activated STAT
Cardiotrophin-1/ CT-1 R alpha + Jak1 STAT1
CT-1 LIF R alpha + Jak2 STAT3
  gp130 Tyk2 STAT5
CLF/CLC CNTF R alpha + Jak1 STAT1
  LIF R alpha + Jak2 STAT3
  gp130 Tyk2  
CNTF CNTF R alpha + Jak1 STAT1
  LIF R alpha + Jak2 STAT3
  gp130 Tyk2  
G-CSF* G-CSF R/ Jak1 STAT1
  CD114 Jak2 STAT3
    Tyk2 STAT5
IL-6 IL-6 R alpha + Jak1 STAT1
  gp130 Jak2 STAT3
    Tyk2  
IL-11 IL-11 R alpha + Jak1 STAT1
  gp130 Jak2 STAT3
    Tyk2  
IL-31 IL-31 RA + Jak1 STAT1
  OSM R beta Jak2 STAT3
      STAT5
Leptin/OB* Leptin R Jak1 STAT1
    Jak2 STAT3
      STAT5
      STAT6
LIF LIF R alpha + Jak1 STAT1
  gp130 Jak2 STAT3
    Tyk2 STAT5
Oncostastin M/ OSM R beta + Jak1 STAT1
OSM gp130 Jak2 STAT3
  LIF R alpha + Tyk2 STAT5
  gp130   STAT6
*G-CSF and Leptin/OB are often associated with the IL-6 family of cytokines because the G-CSF and Leptin receptors are structurally similar to gp130.
Immune Cell Development
Proliferation and Differentiation
Common gamma Chain Receptor Family
Ligand Receptor Complex Activated Jak Activated STAT
IL-2 CD25/IL-2 R alpha + Jak1 STAT1
IL-2 R beta + Jak2 STAT3
Common gamma Chain/IL-2 R gamma Jak3 STAT4
    STAT5
      STAT6
IL-4 IL-4 R alpha + Jak1 STAT1
Common gamma Chain/IL-2 R gamma Jak2 STAT3
IL-4 R alpha + Jak3 STAT4
IL-13 R alpha 1 Tyk2 STAT5
      STAT6
IL-7 IL-7 R alpha/CD127 + Jak1 STAT1
Common gamma Chain/IL-2 R gamma Jak3 STAT2
    STAT3
    STAT5
      STAT6
IL-9 IL-9 R + Jak1 STAT1
Common gamma Chain/IL-2 R gamma Jak3 STAT3
    Tyk2 STAT5
IL-13** IL-13 R alpha 1 + Jak1 STAT1
IL-4 R alpha Jak2 STAT3
  Jak3 STAT5
    Tyk2 STAT6
IL-15 IL-15 R alpha + Jak1 STAT1
IL-2 R beta + Jak2 STAT2
Common gamma Chain/IL-2 R gamma Jak3 STAT3
  Tyk2 STAT4
    STAT5
      STAT6
IL-21 IL-21 R + Jak1 STAT1
Common gamma Chain/IL-2 R gamma Jak3 STAT3
    STAT4
      STAT5
TSLP*** IL-17 R alpha/CD127 + Jak1 STAT1
TSLP R Jak2 STAT3
      STAT5
**IL-13 is often associated with the Common gamma Chain receptor family because it binds to the same receptor complex and possesses similar biologic properties as IL-4.
***TSLP is considered to be a IL-7-related cytokine as it shares several functions and a receptor subunit with IL-7.
Hematopoietic Cell
Growth and Survival
Common beta Chain Receptor Family
Ligand Receptor Complex Activated Jak Activated STAT
GM-CSF GM-CSF R alpha + Jak1 STAT1
Common beta Chain Jak2 STAT3
    STAT5
      STAT6
IL-3 IL-3 R alpha/CD123 + Jak1 STAT1
Common beta Chain Jak2 STAT3
  Tyk2 STAT5
      STAT6
IL-5 IL-5 R alpha/CD125 + Jak1 STAT3
  Common beta Chain Jak2 STAT5
Regulation of Inflammation
T-Cell Dependent Immunity
IL-12 Family
Ligand Receptor Complex Activated Jak Activated STAT
IL-12 IL-12 R beta 1 + Jak2 STAT1
  IL-12 R beta 2 Tyk2 STAT3
      STAT4
      STAT5
      STAT6
IL-23 IL-12 R beta 1 + Jak2 STAT1
  IL-23 R Tyk2 STAT3
      STAT4
      STAT5
IL-27 IL-27 R alpha/WSX-1/ TCCR + Jak1 STAT1
  gp130 Jak2 STAT2
    Tyk2 STAT3
      STAT4
      STAT5
      STAT6
IL-35 IL-12 R beta 2 +   STAT1
  gp130   STAT4
Immune Responses
Anti-viral
Anti-inflammation
IL-10 Family
Ligand Receptor Complex Activated Jak Activated STAT
IL-10 IL-10 R alpha + Jak1 STAT1
  IL-10 R beta Jak2 STAT3
    Tyk2 STAT5
IL-19 IL-20 R alpha + Jak1 STAT3
  IL-20 R beta Jak2  
IL-20 IL-20 R alpha + Jak2 STAT3
  IL-20 R beta   STAT5
  IL-22 R alpha 1 +    
  IL-20 R beta    
IL-22 IL-22 R alpha 1 + Jak1 STAT1
  IL-10 R beta Tyk2 STAT3
      STAT5
IL-24 IL-20 R alpha + Jak1 STAT1
  IL-20 R beta Jak1 STAT1
  IL-22 R alpha 1 + Jak1 STAT1
  IL-20 R beta   STAT3
IL-26/AK155 IL-20 R alpha +   STAT1
  IL-10 R beta   STAT3
IL-28A/IFN- IL-10 R beta + Jak2 STAT1
lambda 2 IL-28 R alpha/IFN-lambda R1   STAT2
      STAT3
IL-28B/IFN- IL-10 R beta +   STAT1
lambda 3 IL-28 R alpha/IFN-lambda R1   STAT2
IL-29/IFN- IL-10 R beta + Jak1 STAT1
lambda 1 IL-28 R alpha/IFN-lambda R1 Tyk2 STAT2
      STAT3
      STAT4
      STAT5
Vascular Remodeling
Cell Migration
G Protein-Coupled Receptors
Ligand Receptor Complex Activated Jak Activated STAT
Angiotensin II AGTR-1 Jak1 STAT1
    Jak2 STAT2
    Tyk2 STAT3
      STAT5
      STAT6
Bradykinin Bradykinin RB2/ Jak2 STAT3
  BDKRB2 Tyk2  
Catecholamines alpha-1A Adrenergic R/ Jak2 STAT1
  ADRA1A Tyk2 STAT3
  alpha-1B Adrenergic R/    
  ADRA1B    
  alpha-1D Adrenergic R/    
  ADRA1D    
CCL2/JE/MCP-1 CCR2 Jak2 STAT1
      STAT3
      STAT5
CCL15/MIP-1 delta CCR1 Jak1 STAT1
      STAT3
Coagulation Factor II/ PAR1 Jak1 STAT1
Thrombin PAR3 Jak2 STAT3
  PAR4 Tyk2 STAT5
CXCL12/SDF-1 CXCR4 Jak1 STAT1
    Jak2 STAT2
    Jak3 STAT3
    Tyk2 STAT4
      STAT5
Platelet-activating PAFR Jak2 STAT1
Factor (PAF)   Tyk2 STAT2
      STAT3
      STAT5
RANTES/CCL5 CCR5 Jak1 STAT1
    Jak2 STAT3
    Jak3 STAT5
Serotonin (5-HT) 5-HT2A Jak1 STAT1
    Jak2 STAT3

Overview of Jak/STAT Signaling Pathway

The Jak/STAT pathway is a putative intracellular signaling pathway that mediates the effects of a large number of cytokines and growth factors. These compounds generally bind to receptors that lack intrinsic kinase activity and thus utilize intracellular enzymes to initiate downstream signaling. This signaling pathway is relatively straightforward as it includes only two main components: Janus Kinases (Jaks) and Signal Transducers and Activators of Transcription (STATs). Jak proteins are non-receptor tyrosine kinases that are constitutively associated with the cytoplasmic domain of receptors. The Jak family includes Jak1, Jak2, Jak3, and Tyk2 (Tyrosine Kinase 2). STAT proteins are latent transcription factors that reside in the cytoplasm until activated via phosphorylation, at which time they translocate to the nucleus. Seven STAT family members have thus far been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

The Jak/STAT pathway is activated following binding of a cytokine or growth factor to its respective receptor. Receptor engagement by a ligand initiates oligomerization of the receptor chains allowing the associated Jak proteins to activate each other by reciprocal tyrosine phosphorylation. The activated Jaks subsequently phosphorylate specific tyrosine residues in the intracellular domains of the receptor. These phosphorylated residues serve as docking sites for the Src homology 2 (SH2)-domain of STAT proteins. Once bound to the receptor, STAT proteins are phosphorylated by Jaks or other kinases, such as Src. Phosphorylated STATs dissociate from the receptor, dimerize, and then translocate to the nucleus where they complex with other nuclear proteins and bind to specific sequences to regulate the expression of target genes.

To date, over 50 cytokines and growth factors have been shown to utilize the four Jak proteins and seven STAT molecules to regulate cell growth, survival differentiation, motility, and immune responses. Activators of the Jak/STAT signaling pathway include type I/II Interferons, the IL-6, IL-10, IL-12, Common gamma Chain, and Common beta Chain families of cytokines, and numerous growth factors that signal through homodimeric hormone receptors, receptor tyrosine kinases, and G protein-coupled receptors. These receptors activate the same general Jak/STAT pathway, though several notable differences occur. STAT1 and STAT2 activated by type I Interferons associate with Interferon Regulatory Factor 9 (IRF9), also called ISGF3-gamma, to form an Interferon-Stimulated Gene Factor-3 (ISGF3) complex. This complex translocates to the nucleus and binds to the interferon-sensitive response element (ISRE). Additionally, Angiotensin II activates the Jak/STAT pathway by two mechanisms. It stimulates the association of Jak proteins, followed by their subsequent phosphorylation, to the Angiotensin II Receptor, Type 1 (AGTR-1) via the tyrosine phosphatase SHP-2. Angiotensin II also stimulates Jak phosphorylation by Proline-rich Tyrosine Kinase 2 (PYK2) via the PLC-IP3-Ca2+- and PLC-DAG-PKC-delta-mediated pathways.

This interactive pathway illustrates a comprehensive list of all Jak and STAT proteins reported to be activated by the different receptor families. It is generally accepted that receptors preferably signal through specific Jak and STAT proteins. However, several factors, such as expression profiles of Jak and STAT proteins, the presence of regulatory molecules, and crosstalk from other signaling pathways, can influence which Jak and STAT proteins are activated by a receptor. To view the references for this information, please visit our Jak/STAT reference table.

To learn more, please visit our Jak/STAT Signaling Research Area.

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