JAK-STAT Signaling
JAK-STAT signaling in vertebrates relies on a network of protein kinases and transcription factors to integrate signals from various receptor systems. The multitude of stimuli include cytokines, growth factors, and hormones, binding of which ultimately effect processes such as immune response regulation and cell growth, survival, and differentiation.
The highly conserved pathway involves essentially three levels of processing of the incoming information depending on the function of the respective components:
- Binding of the ligand to the receptor triggers conformational changes of the receptor molecule(s).
- This steric change of the receptor brings two Janus Kinases (JAK) bound to the receptor or receptor subunits into close proximity, thus enabling trans-phosphorylation. The activated JAKs phosphorylate subsequently additional targets.
- The major phosphorylation targets are Signal transducer and activator of transcription (STAT). These transcription factors are inactive in the cytoplasm until phosphorylation by JAKs. Once the a conserved tyrosine toward the C-terminus of the STAT has been phosphorylated, it can acts as dimerization interface in conjunction with SH2 domains of another STAT. These activated STAT dimers are then translocated to the nucleus and bind to specific DNA motifs to activate target gene transcription.
Besides, negative regulation of these processes takes place on multiple levels:
- Suppressors of cytokine signaling (SOCS) gene transcription is stimulated by activated STATs. SOCS inactivate signaling through binding to the phosphorylated JAKs or receptors or facilitate JAK ubiquitination.
- Protein inhibitor of activated STATs (PIAS) bind to activated STATs and prevent them from binding DNA.
- Protein tyrosine phosphatases (PTP) reverse the activity of JAKs.
The prototypical JAK-STAT signaling pathway is rather linear. There is however considerable crosstalk with other signaling cascades like MAPK pathways and JAK independent STAT phosphorylation through receptor tyrosine kinase (RTKs).
JAK
JAK1 (Janus Kinase 1):
JAK2 (Janus Kinase 2):
TYK2 (Tyrosine Kinase 2):
JAK3 (Janus Kinase 3):
STAT
STAT1 (Signal Transducer and Activator of Transcription 1, 91kDa):
STAT2 (Signal Transducer and Activator of Transcription 2, 113kDa):
STAT3 (Signal Transducer and Activator of Transcription 3 (Acute-Phase Response Factor)):
STAT4 (Signal Transducer and Activator of Transcription 4):
STAT5A (Signal Transducer and Activator of Transcription 5A):
STAT5B (Signal Transducer and Activator of Transcription 5B):
STAT6 (Signal Transducer and Activator of Transcription 6, Interleukin-4 Induced):
SOCS
SOCS1 (Suppressor of Cytokine Signaling 1):
SOCS2 (Suppressor of Cytokine Signaling 2):
CISH (Cytokine Inducible SH2-Containing Protein):
SOCS3 (Suppressor of Cytokine Signaling 3):
SOCS4 (Suppressor of Cytokine Signaling 4):
SOCS5 (Suppressor of Cytokine Signaling 5):
SOCS6 (Suppressor of Cytokine Signaling 6):
PIAS
PIAS1 (Protein Inhibitor of Activated STAT, 1):
PIAS3 (Protein Inhibitor of Activated STAT, 3):
PIAS2 (Protein Inhibitor of Activated STAT, 2):
PIAS4 (Protein Inhibitor of Activated STAT, 4):
PTP
PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):
PTPN6 (Protein-tyrosine Phosphatase 1C):
FYN (FYN Oncogene Related To SRC, FGR, YES):
Src (Proto-oncogene tyrosine-protein kinase Src):
GP130 family
IL6ST (Interleukin 6 Signal Transducer (Gp130, Oncostatin M Receptor)):
IL6R - IL-6 Receptor:
CTF1 - Cardiotrophin 1:
CNTF (Ciliary Neurotrophic Factor):
CNTFR - CNTF Receptor alpha:
IL11 (Interleukin 11):
IL11RA (Interleukin 11 Receptor, alpha):
IL12 (Interleukin 12):
IL12A (Interleukin 12 alpha):
IL12RB1 (Interleukin 12 Receptor beta 1):
IL12RB2 (Interleukin 12 Receptor, beta 2):
IL12B (Interleukin 12 beta):
IL6RA (Interleukin 6 Receptor, alpha):
LEPR - Leptin Receptor:
LIF (Leukemia Inhibitory Factor):
LIFR (Leukemia Inhibitory Factor Receptor alpha):
OSM - Oncostatin M:
OSMR - Oncostatin M Receptor:
Homodimeric receptors
EPO (Erythropoietin):
THPO - Thrombopoietin:
EPOR (Erythropoietin Receptor):
GH1 - Growth Hormone 1:
GH2 - Growth Hormone 2:
GHR - Growth Hormone Receptor:
MPL (Myeloproliferative Leukemia Virus Oncogene):
PRL - Prolactin:
PRLR - Prolactin Receptor:
betaC family
CSF2RB (Colony Stimulating Factor 2 Receptor, Beta, Low-Affinity (Granulocyte-Macrophage)):
CSF2 (Colony Stimulating Factor 2 (Granulocyte-Macrophage)):
IL-3 (Interleukin 3):
CSF2RA (Colony Stimulating Factor 2 Receptor, Alpha, Low-Affinity (Granulocyte-Macrophage)):
IL3RA (Interleukin 3 Receptor, alpha (Low Affinity)):
IL5 (Interleukin 5):
IL5RA (Interleukin 5 Receptor, alpha):
gammaC family
IL2RG (Interleukin 2 Receptor, gamma):
IL2 (Interleukin 2):
IL2RA - CD25:
IL2RB - IL2 Receptor beta:
CD132 - IL2R:
IL13 - IL-13:
IL13RA1 - IL13 Receptor alpha 1:
IL15 (Interleukin 15):
IL15RA (Interleukin 15 Receptor, alpha):
IL21 (Interleukin 21):
IL21R - IL21 Receptor:
IL4R - IL4 Receptor:
IL7 (Interleukin 7):
IL7R (Interleukin 7 Receptor):
IL9 (Interleukin 9):
IL9R - IL9 Receptor:
GPCR
Ang II - Angiotensin II:
GNAQ (Guanine Nucleotide Binding Protein (G Protein), Q Polypeptide):
HTR1A - Serotonin Receptor 1A:
HTR1B - 5HT1B Receptor:
HTR2A (5-Hydroxytryptamine (serotonin) Receptor 2A):
HTR7 (5-Hydroxytryptamine (serotonin) Receptor 7 (Adenylate Cyclase-Coupled)):
AGTR1 - Angiotensin II Type-1 Receptor:
Ang II/III - Angiotensin II/III:
AGT (Angiotensinogen (serpin Peptidase Inhibitor, Clade A, Member 8)):
HTR1D (Serotonin Receptor 1D):
HTR1E - Serotonin Receptor 1E:
HTR1F - 5-Hydroxytryptamine (serotonin) Receptor 1F:
HTR2B - Serotonin Receptor 2B:
HTR4 - Serotonin Receptor 4:
HTR5A - Serotonin Receptor 5A:
HTR6 - Serotonin Receptor 6:
Interferons
IFNAR1 (Interferon (Alpha, beta and Omega) Receptor 1):
IFNA2 (Interferon, alpha 2):
IFNA (Interferon alpha):
IFNAR2 (Interferon alpha/beta Receptor 2):
IRF9 (Interferon Regulatory Factor 9):
IFNA1 (Interferon, alpha 1):
IFNa10 - IFNA10:
IFNA13 (Interferon, alpha 13):
IFNa14 (Interferon, alpha 14):
IFNA16 (Interferon, alpha 16):
IFNa17 - IFNA17:
IFNa21 - IFNA21:
IFNa4 - IFNA4:
IFNA5 (Interferon, alpha 5):
IFNA6 (Interferon, alpha 6):
IFNa7 - IFNA7:
IFNA8 (Interferon, alpha 8):
IFNB1 (Interferon, beta 1, Fibroblast):
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