BioPAX pathway converted from "Activated ERBB2 binds PTK6 (BRK)" in the Reactome database. Activated ERBB2 binds PTK6 (BRK) Activated ERBB2 binds PTK6 (BRK) PTK6 (BRK) is a nonreceptor tyrosine kinase that can bind activated ERBB2 receptor (Xiang et al. 2008). Authored: Orlic-Milacic, Marija, 2016-01-04 Reviewed: Pires, Isabel M, 2016-02-07 Edited: Orlic-Milacic, Marija, 2016-01-04 Converted from EntitySet in Reactome Reactome DB_ID: 1963588 1 plasma membrane GO 0005886 p-ERBB2 heterodimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome http://www.reactome.org Reactome DB_ID: 8848000 1 cytosol GO 0005829 UniProt:Q13882 PTK6 PTK6 PTK6 BRK 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. 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.FUNCTION Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.ACTIVITY REGULATION 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.SUBUNIT 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.TISSUE SPECIFICITY 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.DOMAIN 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.PTM 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.MISCELLANEOUS The inhibitors bind to the ATP-binding pocket.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily. Homo sapiens NCBI Taxonomy 9606 UniProt Q13882 Chain Coordinates 1 EQUAL 451 EQUAL Reactome DB_ID: 8848002 1 p-ERBB2 heterodimers:PTK6 [plasma membrane] p-ERBB2 heterodimers:PTK6 Converted from EntitySet in Reactome Reactome DB_ID: 1963588 1 Reactome DB_ID: 8848000 1 1 EQUAL 451 EQUAL Reactome Database ID Release 81 8848002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8848002 Reactome R-HSA-8848002 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8848002.1 Reactome Database ID Release 81 8847995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847995 Reactome R-HSA-8847995 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847995.2 18719096 Pubmed 2008 Brk is coamplified with ErbB2 to promote proliferation in breast cancer Xiang, Bin Chatti, Kiranam Qiu, Haoqun Lakshmi, B Krasnitz, Alexander Hicks, Jim Yu, Min Miller, WT Muthuswamy, Senthil K Proc. Natl. Acad. Sci. U.S.A. 105:12463-8