P42681 (TXK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase TXK
EC=2.7.10.2

Alternative name(s):
Protein-tyrosine kinase 4
Resting lymphocyte kinase

Gene names

Name:	TXK
Synonyms:	PTK4, RLK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	527 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Contributes also to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. With PARP1 and EEF1A1, TXK forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFNG to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Phosphorylates both PARP1 and EEF1A1. Phosphorylates also key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr-201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Activated by phosphorylation by FYN. Ref.6
Subunit structure	Interacts with PARP1 and EEF1A1. Interacts with SH2D2A By similarity. Ref.8
Subcellular location	Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note: Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation. Translocates into the nucleus and enhances IFN-gamma gene transcription in T-cells. Ref.8
Tissue specificity	Expressed in T-cells and some myeloid cell lines. Expressed in Th1/Th0 cells with IFN-gamma-producing potential. Ref.1 Ref.4
Post-translational modification	Phosphorylated at Tyr-420 by FYN. Autophosphorylation at Tyr-91 is critical for the activation of TXK, leading to the up-regulation of IFN-gamma gene transcription. Ref.6 The cysteine string at the N-terminus is palmitoylated and required for the proper subcellular location By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.
Caution	Unlike the other TEC subfamily members, TXK is activated independently of the activity of phosphatidylinositol 3-kinase, consistent with its lack of a PH domain. Membrane association is performed through palmitoylation at the N-terminus.

Ontologies

Keywords
Biological process	Adaptive immunity Immunity Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Domain	SH2 domain SH3 domain
Ligand	ATP-binding DNA-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Palmitate Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	NK T cell differentiation Inferred from electronic annotation. Source: Compara T cell receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB activation of phospholipase C activity Inferred from sequence or structural similarity. Source: UniProtKB adaptive immune response Inferred from sequence or structural similarity. Source: UniProtKB cytokine production Inferred from sequence or structural similarity. Source: UniProtKB interferon-gamma production Inferred from electronic annotation. Source: Compara interleukin-4 production Inferred from electronic annotation. Source: Compara positive regulation of interferon-gamma production Inferred from direct assay Ref.4Ref.7. Source: UniProtKB positive regulation of interferon-gamma-mediated signaling pathway Inferred from direct assay Ref.7. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.6. Source: UniProtKB regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.7. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Inferred from direct assay Ref.4. Source: UniProtKB nucleus Inferred from direct assay Ref.4. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW RNA polymerase II regulatory region DNA binding Inferred from direct assay Ref.7. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 527

527

Tyrosine-protein kinase TXK

PRO_0000088175

Regions

Domain

82 – 142

61

SH3

Domain

150 – 246

97

SH2

Domain

271 – 527

257

Protein kinase

Nucleotide binding

277 – 285

9

ATP By similarity

Motif

68 – 73

6

Nuclear localization signal Potential

Compositional bias

14 – 19

6

Poly-Cys

Sites

Active site

390

1

Proton acceptor By similarity

Binding site

299

1

ATP By similarity

Amino acid modifications

Modified residue

91

1

Phosphotyrosine; by autocatalysis Ref.6

Modified residue

420

1

Phosphotyrosine; by FYN and autocatalysis Ref.6

Natural variations

Natural variant

45

1

R → H. Ref.1 Ref.11
Corresponds to variant rs7658300 [ dbSNP | Ensembl ].

VAR_028368

Natural variant

63

1

R → C. Ref.11
Corresponds to variant rs41265727 [ dbSNP | Ensembl ].

VAR_041869

Natural variant

336

1

R → Q. Ref.11
Corresponds to variant rs11724347 [ dbSNP | Ensembl ].

VAR_028369

Experimental info

Mutagenesis

91

1

Y → A: Reduces expression levels if IFN-gamma. Ref.6

Mutagenesis

299

1

K → A: Impairs kinase activity. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

527

Helix Strand Turn

Details...

Beta strand

148 – 151

4

Helix

157 – 167

11

Beta strand

175 – 178

4

Beta strand

181 – 189

9

Beta strand

193 – 197

5

Beta strand

200 – 207

8

Beta strand

213 – 218

6

Helix

224 – 231

8

Beta strand

237 – 239

3

Sequences

	Sequence		Length	Mass (Da)
	P42681 [UniParc]. Last modified October 17, 2006. Version 3. Checksum: BCCA081F4155CAA6	FASTA	527	61,258
	10 20 30 40 50 60 MILSSYNTIQ SVFCCCCCCS VQKRQMRTQI SLSTDEELPE KYTQRRRPWL SQLSNKKQSN 70 80 90 100 110 120 TGRVQPSKRK PLPPLPPSEV AEEKIQVKAL YDFLPREPCN LALRRAEEYL ILEKYNPHWW 130 140 150 160 170 180 KARDRLGNEG LIPSNYVTEN KITNLEIYEW YHRNITRNQA EHLLRQESKE GAFIVRDSRH 190 200 210 220 230 240 LGSYTISVFM GARRSTEAAI KHYQIKKNDS GQWYVAERHA FQSIPELIWY HQHNAAGLMT 250 260 270 280 290 300 RLRYPVGLMG SCLPATAGFS YEKWEIDPSE LAFIKEIGSG QFGVVHLGEW RSHIQVAIKA 310 320 330 340 350 360 INEGSMSEED FIEEAKVMMK LSHSKLVQLY GVCIQRKPLY IVTEFMENGC LLNYLRENKG 370 380 390 400 410 420 KLRKEMLLSV CQDICEGMEY LERNGYIHRD LAARNCLVSS TCIVKISDFG MTRYVLDDEY 430 440 450 460 470 480 VSSFGAKFPI KWSPPEVFLF NKYSSKSDVW SFGVLMWEVF TEGKMPFENK SNLQVVEAIS 490 500 510 520 EGFRLYRPHL APMSIYEVMY SCWHEKPEGR PTFAELLRAV TEIAETW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12." Haire R.N., Ohta Y., Lewis J.E., Fu S.M., Kroisel P.M., Litman G.W. Hum. Mol. Genet. 3:897-901(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-45, TISSUE SPECIFICITY. Tissue: Blood.
[2]	"Human Txk: genomic organization, structure and contiguous physical linkage with the Tec gene." Ohta Y., Haire R.N., Amemiya C.T., Litman R.T., Trager T., Riess O., Litman G.W. Oncogene 12:937-942(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Blood.
[3]	"Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4." Schneider H., Schwartzberg P.L., Rudd C.E. Biochem. Biophys. Res. Commun. 252:14-19(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CTLA4, MUTAGENESIS OF LYS-299.
[4]	"Txk, a nonreceptor tyrosine kinase of the Tec family, is expressed in T helper type 1 cells and regulates interferon gamma production in human T lymphocytes." Kashiwakura J., Suzuki N., Nagafuchi H., Takeno M., Takeba Y., Shimoyama Y., Sakane T. J. Exp. Med. 190:1147-1154(1999) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, FUNCTION.
[5]	"Membrane raft-dependent regulation of phospholipase Cgamma-1 activation in T lymphocytes." Veri M.C., DeBell K.E., Seminario M.C., DiBaldassarre A., Reischl I., Rawat R., Graham L., Noviello C., Rellahan B.L., Miscia S., Wange R.L., Bonvini E. Mol. Cell. Biol. 21:6939-6950(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PLCG1.
[6]	"Evidence of autophosphorylation in Txk: Y91 is an autophosphorylation site." Kashiwakura J., Suzuki N., Takeno M., Itoh S., Oku T., Sakane T., Nakajin S., Toyoshima S. Biol. Pharm. Bull. 25:718-721(2002) [PubMed] [Europe PMC] [Abstract] Cited for: AUTOPHOSPHORYLATION, PHOSPHORYLATION AT TYR-91 AND TYR-420, ENZYME REGULATION, MUTAGENESIS OF TYR-91.
[7]	"Txk, a member of nonreceptor tyrosine kinase of Tec family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma gene transcription." Takeba Y., Nagafuchi H., Takeno M., Kashiwakura J., Suzuki N. J. Immunol. 168:2365-2370(2002) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING, FUNCTION.
[8]	"Txk, a member of the non-receptor tyrosine kinase of the Tec family, forms a complex with poly(ADP-ribose) polymerase 1 and elongation factor 1alpha and regulates interferon-gamma gene transcription in Th1 cells." Maruyama T., Nara K., Yoshikawa H., Suzuki N. Clin. Exp. Immunol. 147:164-175(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PARP1 AND EEF1A1, FUNCTION IN PHOSPHORYLATION OF PARP1 AND EEF1A1, SUBCELLULAR LOCATION, FUNCTION AS A TRANSCRIPTION FACTOR.
[9]	"Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk." Readinger J.A., Mueller K.L., Venegas A.M., Horai R., Schwartzberg P.L. Immunol. Rev. 228:93-114(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[10]	"Solution structure of the SH2 domain of human tyrosine-protein kinase TXK." RIKEN structural genomics initiative (RSGI) Submitted (OCT-2006) to the PDB data bank Cited for: STRUCTURE BY NMR OF 140-251.
[11]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] HIS-45; CYS-63 AND GLN-336.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L27071 mRNA. Translation: AAA74557.1.
U34379 , U34367, U34368, U34369, U34370, U34371, U34372, U34373, U34374, U34375, U34376, U34377, U34378 Genomic DNA. Translation: AAB60412.1.

IPI

IPI00000879.

PIR

I84483.

RefSeq

NP_003319.2. NM_003328.2.

UniGene

Hs.479669.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2DM0	NMR	-	A	140-251	[»]

ProteinModelPortal

P42681.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-1493369.

STRING

9606.ENSP00000264316.

PTM databases

PhosphoSite

P42681.

Polymorphism databases

DMDM

116242835.

Proteomic databases

PaxDb

P42681.

PRIDE

P42681.

Protocols and materials databases

DNASU

7294.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264316; ENSP00000264316; ENSG00000074966.

GeneID

7294.

KEGG

hsa:7294.

UCSC

uc003gxx.4. human.

Organism-specific databases

CTD

7294.

GeneCards

GC04M047984.

H-InvDB

HIX0031512.

HGNC

HGNC:12434. TXK.

HPA

HPA043769.

MIM

600058. gene.

neXtProt

NX_P42681.

PharmGKB

PA37090.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233859.

HOVERGEN

HBG008761.

InParanoid

P42681.

KO

K08016.

OMA

PIKWSPP.

OrthoDB

EOG4KSPJK.

PhylomeDB

P42681.

Enzyme and pathway databases

BRENDA

2.7.10.2. 2681.

Gene expression databases

ArrayExpress

P42681.

Bgee

P42681.

CleanEx

HS_TXK.

Genevestigator

P42681.

GermOnline

ENSG00000074966. Homo sapiens.

Family and domain databases

Gene3D

3.30.505.10. 1 hit.

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]

Pfam

PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.
PR00109. TYRKINASE.

SMART

SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.
SSF50044. SH3. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P42681.

ChEMBL

CHEMBL4367.

ChiTaRS

TXK. human.

EvolutionaryTrace

P42681.

GenomeRNAi

7294.

NextBio

28519.

SOURCE

Search...

Entry information

Entry name

TXK_HUMAN

Accession

Primary (citable) accession number: P42681
Secondary accession number(s): Q14220

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	October 17, 2006
Last modified:	May 1, 2013
This is version 131 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.