STAT3

Protein STAT3

Identifiers
signal transducer and activator of transcription 3
HUGO:STAT3 hgnc_id:HGNC:11364 HGNC:11364 ENTREZ:6774 UNIPROT:P40763
HUGO:STAT3
signal transducer and activator of transcription 3 (acute-phase response factor)
HUGO:STAT3 HGNC:11364 ENTREZ:6774 UNIPROT:P40763

Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
Cancer Associated Fibroblasts / INFLAMMATORY_SIGNALING_PATHWAYS
EMT Senescence / EMT_REGULATORS
EMT Senescence / MITOCHONDRIA_OXIDATIVE_STRESS
EMT Senescence / SENESCENCE
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
Regulated Cell Death / ANTIOXIDANT_RESPONSE
Regulated Cell Death / APOPTOSIS
Regulated Cell Death / MITOCHONDRIAL_GENES
Regulated Cell Death / MITOCHONDRIAL_METABOLISM
Regulated Cell Death / OXIDATIVE_PHOSPHOYLATION_AND_TCA_CYCLE
Regulated Cell Death / RCD_GENES
HMC:AVOIDING_IMMUNE_DESTRUCTION
Innate Immunity / IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS
Innate Immunity / IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS

References
CASCADE:IL6
CASCADE:PLAU
PMID:27216177
FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway.
PMID:21840487
ROCK and JAK1/STAT3 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma downstream of IL6 pathway
ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs
STAT3 silencing in CAFs reduces the levels of phosphorylated and total MLC2 protein.
PMID:24857661
TGF-??1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation.
STAT3 inducec CLL2 expression downstream of this signaling.
PMID:23953057
IL6 activates STAT3 in CAFs
PMID:28186502
???21115385, PMID:7543512
???The binding of IL-10 to its receptor activates JAK1
Two tyrosines??? (???Tyr??? ???446??? ???and Tyr??? ???496???) ???of IL-10RA
are phosphorylated by the JAK1,??? ???to which
the transcription factor STAT3??? ???binds via its SH2??? ???domain
and in turn becomes itself phosphorylated.
PMID:10347215
Only JAK1/STAT3 pathway (but not TYK) plays role in
anti-inflammatory action of IL10 in macrophages.
PMID:12223527
Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13.
IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6.
PMID:23124025
Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes
PMID:15218058
Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10
PMID:14607900
FNG inhibits IL10 signalind via STAT1.
STAT1 overexpression prevents STAT3 homodimerization.
PMID:23454751
MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity.
phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC???s suppressive function.
Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3.
PMID:20581311
STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion.
STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein ?? (C/EBP??), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBP?? coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBP?? occupancy during demand-driven granulopoiesis.
PMID:19380816
MDSC-induced immune suppression is mediated by reactive oxygen species (ROS).
STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression
In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses
PMID:20093776
IL6 signaling ilduces STAT3 phosphorylation in MDSC cells.
PMID:20406969
GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro.
PMID:18776941
Expression of VEGF and bFGF, but also IL-1??, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells.
PMID:15573129
Constitutively active STAT3 inhibited the functional maturation of DCs in vitro.
PMID:15356132
The activation of STAT3 by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 was required for the IL-6-mediated suppression of bone-marrow-derived DC activation and/or maturation.
16286017??
IL-6-STAT3 Controls Intracellular MHC Class II ???? Dimer Level through Cathepsin S Activity in Dendritic Cells. IL-6 Stimulation via STAT3 Decreased Cystatin C Expression, Increased the Cathepsin S Activity, and Reduced the MHCII ???? Dimer Level in DCs In Vivo
G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBP?? to C/EBP?? at the c-myc promoter
Stat3 activity is required for tumor factor???induced migration of ECs.
PMID:14670306, PMID:16418395
FLT3 sidnaling in Dcs acts via STAT3
PMID:20237412
IFN-?? regulates expression of homing and angiogenic factors in neutrophils.
IFNB downregulates expression Cxcr4, Vegf, and Mmp9 in neutrophils
additionally Stat3 and c-myc are downregulated by IFN-??.
(STAT3 is known to be required for full activation of the Cxcr4 gene )

STAT3|Y527_pho|active@Cytosol

References
mo_re32:( motility ) PMID:17192274 PMID:27036022
mo_re200:( motility ) PMID:22677902

STAT3|Y527_pho|active@Nucleus

References
mo_re200:( motility ) PMID:22677902
mo_re20:( motility ) PMID:21053359 PMID:18471976 PMID:21084277 PMID:23178297 PMID:20609352 PMID:22073279 PMID:22970020 PMID:21811102 PMID:25139404 PMID:24403062 PMID:27526109 PMID:27222233

STAT3|pho|active@Nucleus

References
em_emtc_emtc_re6( EMT Senescence ):
PMID:21883379
PMID:18297062
TWIST is a downstream target of HIF-1
Hypoxia or HIF-1 induces EMT through the direct activation of TWIST expression
PMID:19412634
Twist is a target of Snail1
PMID:22945800
PMID:21317430
Expression of Twist1 and Snail1 are mutually dependent
Knock-down of Snail1 downregulates Twist1 protein and mRNA
Knock- down of Twist1 interferes with TGFb-mediated induction of Snail1.
PMID:22006115
Alternatively, it has also been reported that Snail1 transcriptionally represses Twist1
PMID:16831886
PMID:18832382
HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression.
HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter.
Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1
HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression
PMID:17403902
Twist1 is a direct downstream target of NKFB.
em_emtc_emtc_re24( EMT Senescence ):
PMID:13130303
Keratin-14, 18, 19, Vimentin are putative direct HIF1 target genes
http://www.omicsonline.org/1948-5956/JCST-03-035.php
Genes induced by HIF-1 in cancer cells include KRT-14, 18, 19, Vimentin, VEGF
PMID:9278421
HIF1 target genes include TGFB3, VEGF
PMID:7768934
VEGF is induced by hypoxia in a HIF1-dependent way
PMID:11528470
Prokinecticin 1 (EG-VEGF) is induced by hypoxia through a potential HIF1-dependent mechanism indicates that this gene is in the same homeostatic cascade as VEGF, Flt1 and erythropoietinPMID:17987801
Expression of Twist positively correlated with up-regulation of VEGF and N-cadherin in hepatocellular carcinoma
PMID:16716598
VEGF transcriptional expression is induced by hypoxia in different cell types under action of y HIF1
em_emtc_emtc_re1123( EMT Senescence ):
PMID:15810077
Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis.
PMID:22943793
Role of TGFB in regulation of cell cycle:
Physiologically, TGFB is a potent inhibitor of cell cycle.
It induces expression of p15INK4B and represses expression of c-Myc
Low levels of c-Myc allows TGFB to induce p15INK4B and p21CIP1 transcription

STAT3|S727_pho@Mitochondrial inner membrane

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
Regulated Cell Death / ANTIOXIDANT_RESPONSE
Regulated Cell Death / APOPTOSIS
Regulated Cell Death / MITOCHONDRIAL_GENES
Regulated Cell Death / MITOCHONDRIAL_METABOLISM
Regulated Cell Death / OXIDATIVE_PHOSPHOYLATION_AND_TCA_CYCLE
Regulated Cell Death / RCD_GENES

References
rc_re70( Regulated Cell Death ):
PMID:19131594
in mouse liver, in mouse pro-B cells, STAT3 is found in mitochondria
mitochondrial STAT3 interacts with NDUFA13
mitochondrial STAT3 necessary for proper activity of complexes I and II of the electron transport chain
STAT3 in mitochondria is preferentially phosphorylated on S727

STAT3|S727_pho@Cytosol

References
rc_re386( Regulated Cell Death ):
PMID:10973499
in vitro reconstitution of the E3-ligase activity, with VHL, elonginB/C, RBX1,CUL2
PMID:18985005
in COS monkey kidney cells and Caki-I human renal carcinoma cells, inhibition of VHL-mediated HIF1A ubiquitinylation and degradation by ectopically expressed constitutively active STAT3

STAT3|S727_unk@Nucleus

References
rc_re106( Regulated Cell Death ):
PMID:18208354
TP53 downregulates the activity of the MCL1 gene promoter in Hela and HEK293
mainly through an unkown mechanism. Critical importance of the -41 to +16 region that correspond to TATA-BP and other basal transcription factors binding
also through down regulation of Sp1
PMID:19808698
in MV4-11 cells, a human biphenotypic B myelomonocytic leukemia that displays FLT3-ITD mutation (constitutive FLT3 signalling), STAT5* siRNA prevents MCL1 expression
PMID:11160159
in large granular lymphocyte high STAT3 activity correlates with MCL1 expression, AG-490 JAK inhibitors induce apoptosis and decreases MCL1 expression.
in NIH3T3, upon v-src, STAT3 dependent expression of MCL1

STAT3|pho|hm2|active@INNATE_IMMUNE_CELL_Cytosol

References
in_re447( Innate Immunity ):
PMID:14607900
FNG inhibits IL10 signalind via STAT1.
STAT1 overexpression prevents STAT3 homodimerization.
in_re429( Innate Immunity ):
PMID:12907458, PMID:12193690
IL10 upregulates expression
of IL4RA in STAT3 dependent manner.
in_re431( Innate Immunity ):
PMID:20435894
IL10 inhibits miR155 expression via STAT3.
in_re569( Innate Immunity ):
PMID:17404308, PMI:17404308
CSF1 upregulates expression of CCL2 probably via CSF1R.
in_re591( Innate Immunity ):
PMID:15465827
BCL3 inhibits expression of IL1B.
in_re629( Innate Immunity ):
PMID:11875494
HMOX1 (HO1) mediates IL-10-induced suppression
of MMP9 expression.
PMID:23390297, PMID:22461508
MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression.
in_re631( Innate Immunity ):
PMID:21372296
HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in
peritoneal macrophages via TLR4-dependent mechanisms.
PMID:21765015
CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production
in_re639( Innate Immunity ):
PMID:20580461
IRF4 regulates expression of some IL4-dependent genes.
IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6,
and downregulate expression IL1RN.
PMID:15218058
Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10
in_re1088( Innate Immunity ):
PMID:12907458
IL10 induces SOCS3 expression in STAT3 dependent manner.
in_re1092( Innate Immunity ):
PMID:12907458, PMID:12907458
STAT3??? ??? directly??? ???up-regulates??? ???BCL3??? ???expression
downstream of??? ???IL10.
NFkB p50 is needfull for BCL3 expression.
in_re1100( Innate Immunity ):
PMID:23124025
IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6
IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6.

STAT3|pho|active@INNATE_IMMUNE_CELL_Cytosol

Identifiers
HUGO:STAT3

References
PMID:???21115385, PMID:7543512
???The binding of IL-10 to its receptor activates JAK1
Two tyrosines??? (???Tyr??? ???446??? ???and Tyr??? ???496???) ???of IL-10RA
are phosphorylated by the JAK1,??? ???to which
the transcription factor STAT3??? ???binds via its SH2??? ???domain
and in turn becomes itself phosphorylated.
PMID:10347215
Only JAK1/STAT3 pathway (but not TYK) plays role in
anti-inflammatory action of IL10 in macrophages.

Modifications:
In compartment: Cytosol

STAT3@Cytosol
STAT3|pho@Cytosol
STAT3|S727_pho@Cytosol
STAT3|pho|active@Cytosol
STAT3|Y527_pho|active@Cytosol

In compartment: INNATE_IMMUNE_CELL_Cytosol

STAT3@INNATE_IMMUNE_CELL_Cytosol
STAT3|pho|active@INNATE_IMMUNE_CELL_Cytosol
STAT3|pho|hm2|active@INNATE_IMMUNE_CELL_Cytosol

In compartment: Mitochondrial inner membrane

STAT3|S727_pho@Mitochondrial inner membrane

In compartment: Nucleus

STAT3|S727_unk@Nucleus
STAT3|Ser727_pho@Nucleus
STAT3|pho|active@Nucleus
STAT3|Y527_pho|active@Nucleus

Participates in complexes:
In compartment: Nucleus

CDK5:EME1:STAT3|Ser727_pho@Nucleus

Participates in reactions:
As Reactant or Product:

As Catalyser: