Reviewed, UniProtKB/Swiss-Prot P40763 (STAT3_HUMAN)

Names and origin

Protein names

Recommended name:
    Signal transducer and activator of transcription 3
Alternative name(s):
    Acute-phase response factor

Gene names

Name:	STAT3
Synonyms:	APRF

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	770 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcription factor that binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL31RA.
Subunit structure	Forms a homodimer or a heterodimer with a related family member (at least STAT1). Interacts with NCOA1, PELP1, SOCS7 and STATIP1. Interacts with HCV core protein. Interacts with IL23R in presence of IL23. Interacts with IL31RA. Interacts with SIPAR By similarity.
Subcellular location	Cytoplasm. Nucleus. Note= Translocated into the nucleus in response to phosphorylation.
Tissue specificity	Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Post-translational modification	Tyrosine phosphorylated in response to IL-6, IL-11, CNTF, LIF, CSF-1, EGF, PDGF, IFN-alpha and OSM. 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.
Involvement in disease	Defects in STAT3 are the cause of hyperimmunoglobulin E recurrent infection syndrome autosomal dominant (AD-HIES) [MIM:147060]; also known as hyper-IgE syndrome or Job syndrome. AD-HIES is a rare disorder of immunity and connective tissue characterized by immunodeficiency, chronic eczema, recurrent Staphylococcal infections, increased serum IgE, eosinophilia, distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures.
Miscellaneous	Involved in the gp130-mediated signaling pathway.
Sequence similarities	Belongs to the transcription factor STAT family. Contains 1 SH2 domain.

Ontologies

Keywords
Biological process	Host-virus interaction Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	SH2 domain
Ligand	DNA-binding
Molecular function	Activator
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	JAK-STAT cascade Traceable author statement. Source: UniProtKB cell motion Traceable author statement. Source: ProtInc cytokine and chemokine mediated signaling pathway Non-traceable author statement. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of transcription from RNA polymerase II promoter Traceable author statement. Source: ProtInc nervous system development Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Ref.1 Traceable author statement. Source: ProtInc nucleus Ref.1 Inferred from direct assay. Source: HGNC
Molecular function	calcium ion binding Inferred from electronic annotation. Source: InterPro hematopoietin/interferon-class (D200-domain) cytokine receptor signal transducer activity Ref.1 Traceable author statement. Source: ProtInc transcription factor activity Ref.1 Traceable author statement. Source: ProtInc transcription factor binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DAXX	Q9UER7	2	EBI-518675,EBI-77321
KHDRBS1	Q07666	1	EBI-518675,EBI-1364
MAP3K7	O43318	1	EBI-518675,EBI-358684
NMI	Q13287	1	EBI-518675,EBI-372942
STAT2	P52630	1	EBI-518675,EBI-1546963

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P40763-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Del-701 (identifier: P40763-2)

The sequence of this isoform differs from the canonical sequence as follows:
     701-701: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 770	770	Signal transducer and activator of transcription 3		PRO_0000182417
Regions
	Domain	580 – 670	91	SH2
Amino acid modifications
	Modified residue	691	1	Phosphoserine
	Modified residue	705	1	Phosphotyrosine
	Modified residue	714	1	Phosphothreonine
	Modified residue	727	1	Phosphoserine
Natural variations
	Alternative sequence	701	1	Missing in isoform Del-701.		VSP_010474
	Natural variant	32	1	Q → K: dbSNP rs1803125.		VAR_018683
	Natural variant	143	1	M → I: dbSNP rs17878478.		VAR_018679
	Natural variant	382	1	R → L in AD-HIES.		VAR_037365
	Natural variant	382	1	R → Q in AD-HIES; loss of function.		VAR_037366
	Natural variant	382	1	R → W in AD-HIES; loss of function.		VAR_037367
	Natural variant	384	1	F → L in AD-HIES.		VAR_037368
	Natural variant	384	1	F → S in AD-HIES.		VAR_037369
	Natural variant	389	1	T → I in AD-HIES; loss of function.		VAR_037370
	Natural variant	423	1	R → Q in AD-HIES.		VAR_037371
	Natural variant	437	1	H → Y in AD-HIES; loss of function.		VAR_037372
	Natural variant	463	1	Missing in AD-HIES; loss of function.		VAR_037373
	Natural variant	561	1	F → Y: dbSNP rs1064116.		VAR_037374
	Natural variant	611	1	S → N in AD-HIES.		VAR_037375
	Natural variant	621	1	F → V in AD-HIES.		VAR_037376
	Natural variant	622	1	T → I in AD-HIES.		VAR_037377
	Natural variant	637	1	V → L in AD-HIES.		VAR_037378
	Natural variant	637	1	V → M in AD-HIES.		VAR_037379
	Natural variant	644	1	Missing in AD-HIES.		VAR_037380
	Natural variant	657	1	Y → C in AD-HIES.		VAR_037381
Experimental info
	Sequence conflict	288	1	Q → H in AAA58374. Ref.1
	Sequence conflict	460	1	P → S in AAA58374. Ref.1
	Sequence conflict	548	1	K → N in AAA58374. Ref.1
	Sequence conflict	667	1	V → L in AAA58374. Ref.1
	Sequence conflict	730	1	T → A in AAA58374. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 7, 2004. Version 2. Checksum: 6C00632211C8012D	FASTA	770	88,068
	10 20 30 40 50 60 MAQWNQLQQL DTRYLEQLHQ LYSDSFPMEL RQFLAPWIES QDWAYAASKE SHATLVFHNL 70 80 90 100 110 120 LGEIDQQYSR FLQESNVLYQ HNLRRIKQFL QSRYLEKPME IARIVARCLW EESRLLQTAA 130 140 150 160 170 180 TAAQQGGQAN HPTAAVVTEK QQMLEQHLQD VRKRVQDLEQ KMKVVENLQD DFDFNYKTLK 190 200 210 220 230 240 SQGDMQDLNG NNQSVTRQKM QQLEQMLTAL DQMRRSIVSE LAGLLSAMEY VQKTLTDEEL 250 260 270 280 290 300 ADWKRRQQIA CIGGPPNICL DRLENWITSL AESQLQTRQQ IKKLEELQQK VSYKGDPIVQ 310 320 330 340 350 360 HRPMLEERIV ELFRNLMKSA FVVERQPCMP MHPDRPLVIK TGVQFTTKVR LLVKFPELNY 370 380 390 400 410 420 QLKIKVCIDK DSGDVAALRG SRKFNILGTN TKVMNMEESN NGSLSAEFKH LTLREQRCGN 430 440 450 460 470 480 GGRANCDASL IVTEELHLIT FETEVYHQGL KIDLETHSLP VVVISNICQM PNAWASILWY 490 500 510 520 530 540 NMLTNNPKNV NFFTKPPIGT WDQVAEVLSW QFSSTTKRGL SIEQLTTLAE KLLGPGVNYS 550 560 570 580 590 600 GCQITWAKFC KENMAGKGFS FWVWLDNIID LVKKYILALW NEGYIMGFIS KERERAILST 610 620 630 640 650 660 KPPGTFLLRF SESSKEGGVT FTWVEKDISG KTQIQSVEPY TKQQLNNMSF AEIIMGYKIM 670 680 690 700 710 720 DATNILVSPL VYLYPDIPKE EAFGKYCRPE SQEHPEADPG SAAPYLKTKF ICVTPTTCSN 730 740 750 760 770 TIDLPMSPRT LDSLMQFGNN GEGAEPSAGG QFESLTFDME LTSECATSPM
	Isoform Del-701 [UniParc]. Checksum: A374A32AB9D28077		769	87,981
	10 20 30 40 50 60 MAQWNQLQQL DTRYLEQLHQ LYSDSFPMEL RQFLAPWIES QDWAYAASKE SHATLVFHNL 70 80 90 100 110 120 LGEIDQQYSR FLQESNVLYQ HNLRRIKQFL QSRYLEKPME IARIVARCLW EESRLLQTAA 130 140 150 160 170 180 TAAQQGGQAN HPTAAVVTEK QQMLEQHLQD VRKRVQDLEQ KMKVVENLQD DFDFNYKTLK 190 200 210 220 230 240 SQGDMQDLNG NNQSVTRQKM QQLEQMLTAL DQMRRSIVSE LAGLLSAMEY VQKTLTDEEL 250 260 270 280 290 300 ADWKRRQQIA CIGGPPNICL DRLENWITSL AESQLQTRQQ IKKLEELQQK VSYKGDPIVQ 310 320 330 340 350 360 HRPMLEERIV ELFRNLMKSA FVVERQPCMP MHPDRPLVIK TGVQFTTKVR LLVKFPELNY 370 380 390 400 410 420 QLKIKVCIDK DSGDVAALRG SRKFNILGTN TKVMNMEESN NGSLSAEFKH LTLREQRCGN 430 440 450 460 470 480 GGRANCDASL IVTEELHLIT FETEVYHQGL KIDLETHSLP VVVISNICQM PNAWASILWY 490 500 510 520 530 540 NMLTNNPKNV NFFTKPPIGT WDQVAEVLSW QFSSTTKRGL SIEQLTTLAE KLLGPGVNYS 550 560 570 580 590 600 GCQITWAKFC KENMAGKGFS FWVWLDNIID LVKKYILALW NEGYIMGFIS KERERAILST 610 620 630 640 650 660 KPPGTFLLRF SESSKEGGVT FTWVEKDISG KTQIQSVEPY TKQQLNNMSF AEIIMGYKIM 670 680 690 700 710 720 DATNILVSPL VYLYPDIPKE EAFGKYCRPE SQEHPEADPG AAPYLKTKFI CVTPTTCSNT 730 740 750 760 IDLPMSPRTL DSLMQFGNNG EGAEPSAGGQ FESLTFDMEL TSECATSPM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway." Akira S., Nishio Y., Inoue M., Wang X.-J., Wei S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimoto T. Cell 77:63-71(1994) [PubMed: 7512451] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT TYR-561. Tissue: Placenta.
[2]	"Highly conserved amino-acid sequence between murine STAT3 and a revised human STAT3 sequence." Della Pietra L., Bressan A., Pezzotti A., Serlupi-Crescenzi O. Gene 213:119-124(1998) [PubMed: 9630560] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	SeattleSNPs program for genomic applications Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ILE-143.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND DEL-701). Tissue: Kidney and Pancreas.
[5]	Della Pietra L., Bressan A., Pezzotti A.R., Serlupi-Crescenzi O. Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 564-704. Tissue: Liver.
[6]	"Requirement of serine phosphorylation for formation of STAT-promoter complexes." Zhang X., Blenis J., Li H.-C., Schindler C., Chen-Kiang S. Science 267:1990-1994(1995) [PubMed: 7701321] [Abstract] Cited for: PHOSPHORYLATION AT SERINE RESIDUES.
[7]	"Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a." Giraud S., Bienvenu F., Avril S., Gascan H., Heery D.M., Coqueret O. J. Biol. Chem. 277:8004-8011(2002) [PubMed: 11773079] [Abstract] Cited for: INTERACTION WITH NCOA1.
[8]	"Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation." Yoshida T., Hanada T., Tokuhisa T., Kosai K., Sata M., Kohara M., Yoshimura A. J. Exp. Med. 196:641-653(2002) [PubMed: 12208879] [Abstract] Cited for: INTERACTION WITH HCV CORE PROTEIN.
[9]	"A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R." Parham C., Chirica M., Timans J., Vaisberg E., Travis M., Cheung J., Pflanz S., Zhang R., Singh K.P., Vega F., To W., Wagner J., O'Farrell A.-M., McClanahan T.K., Zurawski S., Hannum C., Gorman D., Rennick D.M. , Kastelein R.A., de Waal Malefyt R., Moore K.W. J. Immunol. 168:5699-5708(2002) [PubMed: 12023369] [Abstract] Cited for: INTERACTION WITH IL23R.
[10]	"Characterization of the signaling capacities of the novel gp130-like cytokine receptor." Dreuw A., Radtke S., Pflanz S., Lippok B.E., Heinrich P.C., Hermanns H.M. J. Biol. Chem. 279:36112-36120(2004) [PubMed: 15194700] [Abstract] Cited for: FUNCTION, INTERACTION WITH IL31RA.
[11]	"Proline-, glutamic acid-, and leucine-rich protein-1 is essential in growth factor regulation of signal transducers and activators of transcription 3 activation." Manavathi B., Nair S.S., Wang R.-A., Kumar R., Vadlamudi R.K. Cancer Res. 65:5571-5577(2005) [PubMed: 15994929] [Abstract] Cited for: INTERACTION WITH PELP1.
[12]	"Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation." Martens N., Uzan G., Wery M., Hooghe R., Hooghe-Peters E.L., Gertler A. J. Biol. Chem. 280:13817-13823(2005) [PubMed: 15677474] [Abstract] Cited for: INTERACTION WITH SOCS7.
[13]	"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules." Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., Lauffenburger D.A., White F.M. Mol. Cell. Proteomics 4:1240-1250(2005) [PubMed: 15951569] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-705, MASS SPECTROMETRY. Tissue: Epithelium.
[14]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-705, MASS SPECTROMETRY.
[15]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-705, MASS SPECTROMETRY.
[16]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-691, MASS SPECTROMETRY.
[17]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-714 AND SER-727, MASS SPECTROMETRY.
[18]	"STAT3 mutations in the hyper-IgE syndrome." Holland S.M., DeLeo F.R., Elloumi H.Z., Hsu A.P., Uzel G., Brodsky N., Freeman A.F., Demidowich A., Davis J., Turner M.L., Anderson V.L., Darnell D.N., Welch P.A., Kuhns D.B., Frucht D.M., Malech H.L., Gallin J.I., Kobayashi S.D. , Whitney A.R., Voyich J.M., Musser J.M., Woellner C., Schaffer A.A., Puck J.M., Grimbacher B. N. Engl. J. Med. 357:1608-1619(2007) [PubMed: 17881745] [Abstract] Cited for: VARIANTS AD-HIES GLN-382; LEU-382; TRP-382; LEU-384; SER-384; GLN-423; VAL-463 DEL; ASN-611; VAL-621; ILE-622; LEU-637; MET-637; GLN-644 DEL AND CYS-657.
[19]	"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome." Minegishi Y., Saito M., Tsuchiya S., Tsuge I., Takada H., Hara T., Kawamura N., Ariga T., Pasic S., Stojkovic O., Metin A., Karasuyama H. Nature 448:1058-1062(2007) [PubMed: 17676033] [Abstract] Cited for: VARIANTS AD-HIES GLN-382; TRP-382; ILE-389; TYR-437 AND VAL-463 DEL, CHARACTERIZATION OF VARIANTS AD-HIES GLN-382; TRP-382; ILE-389; TYR-437 AND VAL-463 DEL.
+	Additional computationally mapped references.

Web resources

Wikipedia

STAT3 entry

Atlas of Genetics and Cytogenetics in Oncology and Haematology

SeattleSNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	L29277 mRNA. Translation: AAA58374.1. AJ012463 mRNA. Translation: CAA10032.1. AY572796 Genomic DNA. Translation: AAS66986.1. BC000627 mRNA. Translation: AAH00627.1. BC014482 mRNA. Translation: AAH14482.1. AF029311 mRNA. Translation: AAB84254.1.
PIR	A54444.
RefSeq	NP_003141.2. NP_644805.1. NP_998827.1.
UniGene	Hs.463059
3D structure databases
HSSP	HSSP built from PDB template 1BG1 based on UniProtKB P42227.
SMR	P40763. Positions 136-703.
ModBase	Search...
Protein-protein interaction databases
IntAct	P40763.
PTM databases
PhosphoSite	P40763.
Proteomic databases
PeptideAtlas	P40763.
Genome annotation databases
Ensembl	ENSG00000168610. Homo sapiens. [Contig view]
GeneID	6774.
KEGG	hsa:6774.
Organism-specific databases
H-InvDB	HIX0013840.
HGNC	HGNC:11364. STAT3.
HPA	CAB003859. HPA001671.
MIM	102582. gene. 147060. phenotype.
Orphanet	2314. Job syndrome.
PharmGKB	PA337.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOVERGEN	P40763.
Gene expression databases
ArrayExpress	P40763.
CleanEx	HS_STAT3.
GermOnline	ENSG00000168610. Homo sapiens.
Family and domain databases
InterPro	IPR011992. EF-Hand_type. IPR000980. SH2.