UniProt functional annotation for P42227



	UniProt functional annotation for P42227

UniProt code: P42227.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (By similarity). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (By similarity). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (By similarity). Activated by IL31 through IL31RA (By similarity). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (By similarity). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (By similarity). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (PubMed:12594516). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:16825198). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (By similarity). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (PubMed:20215569). Plays an important role in host defense in methicillin-resistant S.aureus lung infection by regulating the expression of the antimicrobial lectin REG3G (PubMed:23401489). {ECO:0000250|UniProtKB:P40763, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:12594516, ECO:0000269|PubMed:16825198, ECO:0000269|PubMed:20215569, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23401489}.

Subunit: Forms a homodimer or a heterodimer with a related family member (at least STAT1). Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1. Interacts with IL23R in presence of IL23. Interacts (via SH2 domain) with NLK. Interacts with ARL2BP; the interaction is enhanced by LIF and JAK1 expression (By similarity). Interacts with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear import (By similarity). Interacts with CAV2; the interaction is increased on insulin-induced tyrosine phosphorylation of CAV2 and leads to STAT3 activation (By similarity). Interacts with ARL2BP; interaction is enhanced with ARL2. Interacts with NEK6 (By similarity). Binds to CDK9 when activated and nuclear. Interacts with BMX. Interacts with ZIPK/DAPK3. Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. In prostate cancer cells, interacts with PRKCE and promotes DNA binding activity of STAT3. Interacts with STMN3, antagonizing its microtubule- destabilizing activity. Interacts with the 'Lys-129' acetylated form of BIRC5/survivin. Interacts with FER. Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with FGFR4 (By similarity). Interacts with INPP5F; the interaction is independent of STAT3 Tyr-705 phosphorylation status (By similarity). Interacts with OCAD1 (PubMed:23972987). Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB (By similarity). Interacts and may form heterodimers with NHLH1 (PubMed:18356286). {ECO:0000250|UniProtKB:P40763, ECO:0000250|UniProtKB:P52631, ECO:0000269|PubMed:10878010, ECO:0000269|PubMed:10954736, ECO:0000269|PubMed:11553624, ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:15919823, ECO:0000269|PubMed:16401721, ECO:0000269|PubMed:18234692, ECO:0000269|PubMed:18356286, ECO:0000269|PubMed:20595392, ECO:0000269|PubMed:23972987, ECO:0000269|PubMed:9388184, ECO:0000269|Ref.18}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:P40763}. Nucleus {ECO:0000250|UniProtKB:P40763}. Note=Predominantly present in the cytoplasm without stimuli. Upon leukemia inhibitory factor (LIF) stimulation, accumulates in the nucleus. The complex composed of BART and ARL2 plays an important role in the nuclear translocation and retention of STAT3 (By similarity). Shuttles between the nucleus and the cytoplasm. Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4. Constitutive nuclear presence is independent of tyrosine phosphorylation. {ECO:0000250}.

Tissue specificity: STAT3A is seen in the liver, spleen, and kidney. STAT3B is also detected in the liver, although in a much less abundant manner. Expressed in the lung and an increase in expression levels seen during methicillin-resistant S.aureus infection. {ECO:0000269|PubMed:23401489}.

Ptm: Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, CNTF, LIF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha, LEP and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Serine phosphorylation is important for the formation of stable DNA-binding STAT3 homodimers and maximal transcriptional activity. ARL2BP may participate in keeping the phosphorylated state of STAT3 within the nucleus. Tyrosine phosphorylated upon stimulation with EGF. Upon LPS challenge, phosphorylated within the nucleus by IRAK1 (By similarity). Upon UV-A treatment, phosphorylated on Ser-727 by RPS6KA5 (By similarity). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling (By similarity). Phosphorylation at Tyr-705 by PTK6 or FER leads to an increase of its transcriptional activity (By similarity). {ECO:0000250|UniProtKB:P40763, ECO:0000269|PubMed:10878010, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11553624, ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:16825198, ECO:0000269|PubMed:20595392, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:23401489, ECO:0000269|PubMed:7543024}.

Ptm: Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. {ECO:0000250|UniProtKB:P40763}.

Ptm: Some lysine residues are oxidized to allysine by LOXL3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. {ECO:0000250|UniProtKB:P40763}.

Ptm: (Microbial infection) Phosphorylated on Tyr-705 in the presence of S.typhimurium SarA. {ECO:0000269|PubMed:29924996}.

Disruption phenotype: Early embryonic lethality, day 6.5-7.5. Conditional, tissue specific mutants are variably viable and show diverse defects including obesity, diabetes, thermal dysregulation and infertility. {ECO:0000269|PubMed:20215569, ECO:0000269|PubMed:9108058}.

Miscellaneous: Involved in the gp130-mediated signaling pathway.

Similarity: Belongs to the transcription factor STAT family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (By similarity). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (By similarity). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes (By similarity). Activated by IL31 through IL31RA (By similarity). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (By similarity). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (By similarity). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (PubMed:12594516). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:16825198). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (By similarity). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (PubMed:20215569). Plays an important role in host defense in methicillin-resistant S.aureus lung infection by regulating the expression of the antimicrobial lectin REG3G (PubMed:23401489). {ECO:0000250\|UniProtKB:P40763, ECO:0000269\|PubMed:11294897, ECO:0000269\|PubMed:12594516, ECO:0000269\|PubMed:16825198, ECO:0000269\|PubMed:20215569, ECO:0000269\|PubMed:23084476, ECO:0000269\|PubMed:23401489}.


Subunit:		Forms a homodimer or a heterodimer with a related family member (at least STAT1). Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1. Interacts with IL23R in presence of IL23. Interacts (via SH2 domain) with NLK. Interacts with ARL2BP; the interaction is enhanced by LIF and JAK1 expression (By similarity). Interacts with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear import (By similarity). Interacts with CAV2; the interaction is increased on insulin-induced tyrosine phosphorylation of CAV2 and leads to STAT3 activation (By similarity). Interacts with ARL2BP; interaction is enhanced with ARL2. Interacts with NEK6 (By similarity). Binds to CDK9 when activated and nuclear. Interacts with BMX. Interacts with ZIPK/DAPK3. Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. In prostate cancer cells, interacts with PRKCE and promotes DNA binding activity of STAT3. Interacts with STMN3, antagonizing its microtubule- destabilizing activity. Interacts with the 'Lys-129' acetylated form of BIRC5/survivin. Interacts with FER. Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with FGFR4 (By similarity). Interacts with INPP5F; the interaction is independent of STAT3 Tyr-705 phosphorylation status (By similarity). Interacts with OCAD1 (PubMed:23972987). Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB (By similarity). Interacts and may form heterodimers with NHLH1 (PubMed:18356286). {ECO:0000250\|UniProtKB:P40763, ECO:0000250\|UniProtKB:P52631, ECO:0000269\|PubMed:10878010, ECO:0000269\|PubMed:10954736, ECO:0000269\|PubMed:11553624, ECO:0000269\|PubMed:15004007, ECO:0000269\|PubMed:15919823, ECO:0000269\|PubMed:16401721, ECO:0000269\|PubMed:18234692, ECO:0000269\|PubMed:18356286, ECO:0000269\|PubMed:20595392, ECO:0000269\|PubMed:23972987, ECO:0000269\|PubMed:9388184, ECO:0000269\|Ref.18}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:P40763}. Nucleus {ECO:0000250\|UniProtKB:P40763}. Note=Predominantly present in the cytoplasm without stimuli. Upon leukemia inhibitory factor (LIF) stimulation, accumulates in the nucleus. The complex composed of BART and ARL2 plays an important role in the nuclear translocation and retention of STAT3 (By similarity). Shuttles between the nucleus and the cytoplasm. Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4. Constitutive nuclear presence is independent of tyrosine phosphorylation. {ECO:0000250}.
Tissue specificity:		STAT3A is seen in the liver, spleen, and kidney. STAT3B is also detected in the liver, although in a much less abundant manner. Expressed in the lung and an increase in expression levels seen during methicillin-resistant S.aureus infection. {ECO:0000269\|PubMed:23401489}.
Ptm:		Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, CNTF, LIF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha, LEP and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Serine phosphorylation is important for the formation of stable DNA-binding STAT3 homodimers and maximal transcriptional activity. ARL2BP may participate in keeping the phosphorylated state of STAT3 within the nucleus. Tyrosine phosphorylated upon stimulation with EGF. Upon LPS challenge, phosphorylated within the nucleus by IRAK1 (By similarity). Upon UV-A treatment, phosphorylated on Ser-727 by RPS6KA5 (By similarity). Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling (By similarity). Phosphorylation at Tyr-705 by PTK6 or FER leads to an increase of its transcriptional activity (By similarity). {ECO:0000250\|UniProtKB:P40763, ECO:0000269\|PubMed:10878010, ECO:0000269\|PubMed:11294897, ECO:0000269\|PubMed:11553624, ECO:0000269\|PubMed:15004007, ECO:0000269\|PubMed:16825198, ECO:0000269\|PubMed:20595392, ECO:0000269\|PubMed:21135090, ECO:0000269\|PubMed:23401489, ECO:0000269\|PubMed:7543024}.
Ptm:		Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. {ECO:0000250\|UniProtKB:P40763}.
Ptm:		Some lysine residues are oxidized to allysine by LOXL3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. {ECO:0000250\|UniProtKB:P40763}.
Ptm:		(Microbial infection) Phosphorylated on Tyr-705 in the presence of S.typhimurium SarA. {ECO:0000269\|PubMed:29924996}.
Disruption phenotype:		Early embryonic lethality, day 6.5-7.5. Conditional, tissue specific mutants are variably viable and show diverse defects including obesity, diabetes, thermal dysregulation and infertility. {ECO:0000269\|PubMed:20215569, ECO:0000269\|PubMed:9108058}.
Miscellaneous:		Involved in the gp130-mediated signaling pathway.
Similarity:		Belongs to the transcription factor STAT family. {ECO:0000305}.