Protein-tyrosine kinase 6

UniProt Q13882 Organism Homo sapiens Gene BRK, PTK6 EC 2.7.10.2

Also known as: BRK, PTK6

Function

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. Phosphorylates the GTPase-activating protein ARAP1 following EGF stimulation which enhances EGFR signaling by delaying EGFR down-regulation. Also associates 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.

Classification

Family (Pfam): PF07714 PK_Tyr_Ser-Thr, PF00017 SH2, PF00018 SH3_1
InterPro: Kinase-like_dom_sf, Non-receptor_tyrosine_kinases, Prot_kinase_dom, Protein_kinase_ATP_BS, PTK6_SH2, Ser-Thr/Tyr_kinase_cat_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain, Tyr_kinase_AS, Tyr_kinase_cat_dom
Functional cluster: Cytochrome P450 & Heme Enzymes

Experimental structures · PDB · 9

1RJA NMR
2KGT NMR
5D7V X-ray 2.33A
5DA3 X-ray 1.70A
5H2U X-ray 2.24A
6CZ2 X-ray 2.50A
6CZ3 X-ray 1.80A
6CZ4 X-ray 1.50A
8S1C X-ray 1.75A

A predicted model is available from AlphaFold.

Gene Ontology · 28

Drugs targeting this protein · 1

VANDETANIB inhibitor

Related proteins · sequence + function similarity

Protein-tyrosine kinase 6 0.96
Tyrosine-protein kinase Srms 0.95
Tyrosine-protein kinase Srms 0.93
Megakaryocyte-associated tyrosine-protein kinase 0.92
Megakaryocyte-associated tyrosine-protein kinase 0.91
Tyrosine-protein kinase TXK 0.90
Tyrosine-protein kinase FRK 0.89
Megakaryocyte-associated tyrosine-protein kinase 0.89
Tyrosine-protein kinase Blk 0.88
Tyrosine-protein kinase CSK 0.88
Tyrosine-protein kinase Blk 0.88
Tyrosine-protein kinase CSK 0.87

Co-cited proteins · studied together in the literature

Protein-tyrosine kinase 6 3 shared papers
Signal-transducing adaptor protein 2 1 shared papers
Rho GTPase-activating protein 35 1 shared papers
Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 1 shared papers
KH domain-containing, RNA-binding, signal transduction-associated protein 1 2 shared papers
Insulin receptor substrate 4 1 shared papers
Signal transducer and activator of transcription 5B 1 shared papers
Splicing factor, proline- and glutamine-rich 1 shared papers
Paxillin 1 shared papers
Receptor tyrosine-protein kinase erbB-2 1 shared papers
KH domain-containing, RNA-binding, signal transduction-associated protein 2 1 shared papers
Signal transducer and activator of transcription 3 1 shared papers

Literature · 36 cited papers

Co-crystal structures of PTK6: With Dasatinib at 2.24 A, with novel imidazo[1,2-a]pyrazin-8-amine derivative inhibitor at 1.70 A resolution. Biochem. Biophys. Res. Commun. · 2017
Crystal structure of the kinase domain of human protein tyrosine kinase 6 (PTK6) at 2.33 A resolution. Biochem. Biophys. Res. Commun. · 2016
The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of beta-catenin. PLoS ONE · 2011
PTK6 inhibits down-regulation of EGF receptor through phosphorylation of ARAP1. J. Biol. Chem. · 2010
Building a better understanding of the intracellular tyrosine kinase PTK6 - BRK by BRK. Biochim. Biophys. Acta · 2010
Identification of beta-catenin as a target of the intracellular tyrosine kinase PTK6. J. Cell Sci. · 2010
BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest. Cell. Signal. · 2009
Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res. · 2008
Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc. Natl. Acad. Sci. U.S.A. · 2008
Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell · 2008
Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma. Mol. Cancer Res. · 2008
Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. · 2007
… and 24 more in the literature graph

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