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UniProtKB - Q13882 (PTK6_HUMAN)

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Protein

Protein-tyrosine kinase 6

Gene

PTK6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.
Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.

Miscellaneous

The inhibitors bind to the ATP-binding pocket.1 Publication

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation3 Publications

Enzyme regulationi

Activated by EGF, NRG1 and IGF1. Inhibited by SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region. Interaction between Trp-184 within SH2-TK linker region and the catalytic domain appears essential for positive regulation of kinase activity.5 Publications

Kineticsi

  1. KM=83 µM for ATP1 Publication
  1. Vmax=37 nmol/min/mg enzyme1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei219ATPPROSITE-ProRule annotation2 Publications1
Active sitei312Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi197 – 205ATPPROSITE-ProRule annotation9

GO - Molecular functioni

Complete GO annotation...

GO - Biological processi

  • cell migration Source: UniProtKB
  • cellular response to retinoic acid Source: BHF-UCL
  • ERBB2 signaling pathway Source: Reactome
  • innate immune response Source: GO_Central
  • intestinal epithelial cell differentiation Source: Ensembl
  • negative regulation of growth Source: Ensembl
  • negative regulation of protein tyrosine kinase activity Source: UniProtKB
  • negative regulation of signal transduction Source: Reactome
  • peptidyl-tyrosine autophosphorylation Source: GO_Central
  • positive regulation of cell cycle Source: Reactome
  • positive regulation of epidermal growth factor receptor signaling pathway Source: Reactome
  • positive regulation of neuron projection development Source: BHF-UCL
  • protein autophosphorylation Source: UniProtKB
  • protein phosphorylation Source: ProtInc
  • regulation of cell proliferation Source: GO_Central
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
  • tyrosine phosphorylation of STAT protein Source: UniProtKB
Complete GO annotation...

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-187577. SCF(Skp2)-mediated degradation of p27/p21.
R-HSA-69231. Cyclin D associated events in G1.
R-HSA-8847993. ERBB2 Activates PTK6 Signaling.
R-HSA-8849468. PTK6 Regulates Proteins Involved in RNA Processing.
R-HSA-8849469. PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
R-HSA-8849470. PTK6 Regulates Cell Cycle.
R-HSA-8849471. PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.
R-HSA-8849472. PTK6 Down-Regulation.
R-HSA-8849473. PTK6 Expression.
R-HSA-8849474. PTK6 Activates STAT3.
R-HSA-8857538. PTK6 promotes HIF1A stabilization.
SignaLinkiQ13882.
SIGNORiQ13882.

Names & Taxonomyi

Protein namesi
Recommended name:
Protein-tyrosine kinase 6 (EC:2.7.10.23 Publications)
Alternative name(s):
Breast tumor kinase
Tyrosine-protein kinase BRK
Gene namesi
Name:PTK6
Synonyms:BRK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

HGNCiHGNC:9617. PTK6.

Subcellular locationi

  • Cytoplasm
  • Nucleus
  • Cell projection › ruffle
  • Membrane By similarity

    • Note: Colocalizes with KHDRBS1, KHDRBS2 or KHDRBS3, within the nucleus. Nuclear localization in epithelial cells of normal prostate but cytoplasmic localization in cancer prostate.

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: HPA
  • extrinsic component of cytoplasmic side of plasma membrane Source: GO_Central
  • nuclear body Source: HPA
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • plasma membrane Source: HPA
  • ruffle Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell projection, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi44W → A: Strong decrease in STAP2 phosphorylation. Markedly decreased interaction between SH3 domain the linker region. 2 Publications1
Mutagenesisi66Y → A: Decrease in STAP2 phosphorylation. 1 Publication1
Mutagenesisi105R → L: Decrease in STAP2 phosphorylation. 1 Publication1
Mutagenesisi184W → A: Abrogates interaction between PTK6-domain kinase and PTK6-linker. Abrogates autophosphorylation and phosphorylation of KHDRBS1. 1 Publication1
Mutagenesisi219K → M: Abolishes kinase activity and cell transformation, and phosphorylation of STAP2. 3 Publications1
Mutagenesisi219K → R: Abolishes kinase activity. 1 Publication1
Mutagenesisi342Y → A: 3-fold lower specific kinase activity. Decreased, but still significant, autophosphorylation. Decreased, but still significant, autophosphorylation; when associated with A-447. 1 Publication1
Mutagenesisi447Y → F: Decrease in transforming potential and increase in the kinase activity level. Decreased, but still significant, autophosphorylation; when associated with A-342. 3 Publications1

Organism-specific databases

DisGeNETi5753.
OpenTargetsiENSG00000101213.
PharmGKBiPA33960.

Chemistry databases

ChEMBLiCHEMBL4601.
DrugBankiDB05294. Vandetanib.
GuidetoPHARMACOLOGYi2182.

Polymorphism and mutation databases

BioMutaiPTK6.
DMDMi8928302.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000881331 – 451Protein-tyrosine kinase 6Add BLAST451

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei13Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei61Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei66Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei114Phosphotyrosine; by autocatalysisCombined sources1 Publication1
Modified residuei342Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei351Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei447Phosphotyrosine1 Publication1

Post-translational modificationi

Autophosphorylated. Autophosphorylation of Tyr-342 leads to an increase of kinase activity. Tyr-447 binds to the SH2 domain when phosphorylated and negatively regulates kinase activity.4 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ13882.
PaxDbiQ13882.
PeptideAtlasiQ13882.
PRIDEiQ13882.

PTM databases

iPTMnetiQ13882.
PhosphoSitePlusiQ13882.

Expressioni

Tissue specificityi

Epithelia-specific. Very high level in colon and high levels in small intestine and prostate, and low levels in some fetal tissues. Not expressed in breast or ovarian tissue but expressed in high percentage of breast and ovarian cancers. Also overexpressed in some metastatic melanomas, lymphomas, colon cancers, squamous cell carcinomas and prostate cancers. Also found in melanocytes. Not expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 2 is present in prostate epithelial cell lines derived from normal prostate and prostate adenocarcinomas, as well as in a variety of cell lines.4 Publications

Gene expression databases

BgeeiENSG00000101213.
CleanExiHS_PTK6.
GenevisibleiQ13882. HS.

Organism-specific databases

HPAiCAB032952.
HPA036070.
HPA036071.

Interactioni

Subunit structurei

Interacts with GAP-A.p65 (By similarity). Interacts (via SH3 and SH2 domains) with KHDRBS1. Interacts (via SH3 and SH2 domains) with phosphorylated IRS4. Interacts with ADAM15. Interacts (via SH3 domain) with SFPQ. Interacts with EGFR and ERBB2. Interacts with STAP2. Interacts with PNX. Interacts with SFPQ. Interacts with PTK/ATK. Interacts with CTNNB1.By similarity10 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • receptor binding Source: GO_Central
Complete GO annotation...

Protein-protein interaction databases

BioGridi111720. 23 interactors.
DIPiDIP-39785N.
IntActiQ13882. 29 interactors.
MINTiMINT-1494499.
STRINGi9606.ENSP00000217185.

Chemistry databases

BindingDBiQ13882.

Structurei

Secondary structure

1451
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi12 – 14Combined sources3
Beta strandi35 – 40Combined sources6
Beta strandi45 – 50Combined sources6
Beta strandi56 – 62Combined sources7
Turni64 – 66Combined sources3
Beta strandi67 – 70Combined sources4
Helixi85 – 92Combined sources8
Beta strandi102 – 106Combined sources5
Beta strandi108 – 112Combined sources5
Beta strandi114 – 118Combined sources5
Beta strandi125 – 131Combined sources7
Beta strandi133 – 135Combined sources3
Beta strandi137 – 140Combined sources4
Beta strandi143 – 147Combined sources5
Helixi148 – 157Combined sources10
Beta strandi162 – 164Combined sources3
Helixi188 – 190Combined sources3
Beta strandi191 – 200Combined sources10
Beta strandi203 – 210Combined sources8
Turni211 – 213Combined sources3
Beta strandi214 – 221Combined sources8
Helixi223 – 225Combined sources3
Helixi233 – 240Combined sources8
Beta strandi250 – 254Combined sources5
Beta strandi256 – 264Combined sources9
Helixi272 – 277Combined sources6
Turni281 – 283Combined sources3
Helixi286 – 305Combined sources20
Helixi315 – 317Combined sources3
Beta strandi318 – 320Combined sources3
Helixi322 – 324Combined sources3
Beta strandi326 – 328Combined sources3
Helixi333 – 336Combined sources4
Helixi339 – 343Combined sources5
Helixi345 – 348Combined sources4
Helixi349 – 352Combined sources4
Helixi356 – 361Combined sources6
Helixi366 – 380Combined sources15
Turni381 – 384Combined sources4
Helixi393 – 401Combined sources9
Helixi414 – 423Combined sources10
Helixi428 – 430Combined sources3
Helixi434 – 442Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1RJANMR-A75-174[»]
2KGTNMR-A1-72[»]
5D7VX-ray2.33A/B/C/D185-446[»]
5DA3X-ray1.70A185-446[»]
5H2UX-ray2.24A/B/C/D185-446[»]
ProteinModelPortaliQ13882.
SMRiQ13882.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ13882.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini11 – 72SH3PROSITE-ProRule annotationAdd BLAST62
Domaini78 – 170SH2PROSITE-ProRule annotationAdd BLAST93
Domaini191 – 445Protein kinasePROSITE-ProRule annotationAdd BLAST255

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni171 – 190LinkerAdd BLAST20

Domaini

The SH3 domain plays a major role in substrate interactions. The SH2 domain of PTK6 plays a role in protein-protein interactions, but is likely more important for the regulation of catalytic activity.

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily.PROSITE-ProRule annotation

Keywords - Domaini

SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118938.
HOGENOMiHOG000233858.
HOVERGENiHBG008761.
InParanoidiQ13882.
KOiK08894.
OMAiVRHYKIW.
OrthoDBiEOG091G0596.
PhylomeDBiQ13882.
TreeFamiTF351634.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiView protein in InterPro
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_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.
PfamiView protein in Pfam
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTiView protein in SMART
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiView protein in 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.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q13882-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MVSRDQAHLG PKYVGLWDFK SRTDEELSFR AGDVFHVARK EEQWWWATLL 
        60         70         80         90        100
DEAGGAVAQG YVPHNYLAER ETVESEPWFF GCISRSEAVR RLQAEGNATG 
       110        120        130        140        150
AFLIRVSEKP SADYVLSVRD TQAVRHYKIW RRAGGRLHLN EAVSFLSLPE 
       160        170        180        190        200
LVNYHRAQSL SHGLRLAAPC RKHEPEPLPH WDDWERPREE FTLCRKLGSG 
       210        220        230        240        250
YFGEVFEGLW KDRVQVAIKV ISRDNLLHQQ MLQSEIQAMK KLRHKHILAL 
       260        270        280        290        300
YAVVSVGDPV YIITELMAKG SLLELLRDSD EKVLPVSELL DIAWQVAEGM 
       310        320        330        340        350
CYLESQNYIH RDLAARNILV GENTLCKVGD FGLARLIKED VYLSHDHNIP 
       360        370        380        390        400
YKWTAPEALS RGHYSTKSDV WSFGILLHEM FSRGQVPYPG MSNHEAFLRV 
       410        420        430        440        450
DAGYRMPCPL ECPPSVHKLM LTCWCRDPEQ RPCFKALRER LSSFTSYENP 

T
Length:451
Mass (Da):51,834
Last modified:November 1, 1996 - v1
Checksum:iCDCAC0EE242E1BD7
GO
Isoform 2 (identifier: Q13882-2) [UniParc]FASTAAdd to basket
Also known as: ALT-PTK6, LambdaM5

The sequence of this isoform differs from the canonical sequence as follows:
     78-134: WFFGCISRSE...RHYKIWRRAG → AGHAGCAALQ...AGRALPEARA
     135-451: Missing.

Show »
Length:134
Mass (Da):14,465
Checksum:i7F350D1F4D13EBE9
GO

Sequence cautioni

The sequence BAG62908 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04176016L → F in a renal papillary sample; somatic mutation. 1 Publication1
Natural variantiVAR_041761436A → T1 PublicationCorresponds to variant dbSNP:rs56145017Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04206678 – 134WFFGC…WRRAG → AGHAGCAALQDLAACRGPAA PERGGVLPQPARACELPQGP EPVPRPAAGRALPEARA in isoform 2. 2 PublicationsAdd BLAST57
Alternative sequenceiVSP_042067135 – 451Missing in isoform 2. 2 PublicationsAdd BLAST317

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X78549 mRNA. Translation: CAA55295.1.
U61412
, U61406, U61407, U61408, U61409, U61410, U61411 Genomic DNA. Translation: AAC34935.1.
AK315232 mRNA. Translation: BAG37660.1.
AK301364 mRNA. Translation: BAG62908.1. Sequence problems.
AL121829 Genomic DNA. No translation available.
BC035843 mRNA. Translation: AAH35843.1.
CCDSiCCDS13524.1. [Q13882-1]
CCDS74750.1. [Q13882-2]
PIRiS49016.
RefSeqiNP_001243287.1. NM_001256358.1. [Q13882-2]
NP_005966.1. NM_005975.3. [Q13882-1]
UniGeneiHs.51133.

Genome annotation databases

EnsembliENST00000217185; ENSP00000217185; ENSG00000101213. [Q13882-2]
ENST00000542869; ENSP00000442460; ENSG00000101213. [Q13882-1]
GeneIDi5753.
KEGGihsa:5753.
UCSCiuc002yfg.5. human. [Q13882-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiPTK6_HUMAN
AccessioniPrimary (citable) accession number: Q13882
Secondary accession number(s): B2RCR3, B4DW46, Q58F01
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: June 7, 2017
This is version 182 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families