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Human Phosphatases
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Statistics

241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update:
11 Mar, 2019
last maintenance update:
01 Sep, 2023

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PTK6

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	PTK6 (QuickGO)	Interactive visualization of PTK6 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 5DA3
Synonyms	PTK6, BRK,
Protein Name	PTK6
Alternative Name(s)	Protein-tyrosine kinase 6;2.7.10.2 {ECO:0000269\|PubMed:12121988, ECO:0000269\|PubMed:27480927, ECO:0000269\|PubMed:27993680};Breast tumor kinase;Tyrosine-protein kinase BRK;
Protein Family	Belongs to the protein kinase superfamily Tyr proteinkinase family BRK/PTK6/SIK subfamily
EntrezGene ID	5753 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q13882 (protein sequence)
Enzyme Class	2.7.10.2 (BRENDA )
Molecular Weight	51834 Dalton
Protein Length	451 amino acids (AA)
Genome Browsers	NCBI \|
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree

Domain organization, Expression, Diseases

Localization, Function, Catalytic activity and Sequence

Localization (UniProt annotation)
Cytoplasm Nucleus Cell projection, ruffleMembrane Note=Colocalizes with KHDRBS1, KHDRBS2 orKHDRBS3, within the nucleus Nuclear localization in epithelialcells of normal prostate but cytoplasmic localization in cancerprostate
Function (UniProt annotation)
Non-receptor tyrosine-protein kinase implicated in theregulation of a variety of signaling pathways that control thedifferentiation and maintenance of normal epithelia, as well astumor growth Function seems to be context dependent and differdepending on cell type, as well as its intracellular localizationA number of potential nuclear and cytoplasmic substrates have beenidentified 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 Associatesalso with a variety of proteins that are likely upstream of PTK6in various signaling pathways, or for which PTK6 may play anadapter-like role These proteins include ADAM15, EGFR, ERBB2,ERBB3 and IRS4 In normal or non-tumorigenic tissues, PTK6promotes cellular differentiation and apoptosis In tumors PTK6contributes to cancer progression by sensitizing cells tomitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion Association withEGFR, ERBB2, ERBB3 may contribute to mammary tumor development andgrowth through enhancement of EGF-induced signaling via BTK/AKTand PI3 kinase Contributes to migration and proliferation bycontributing to EGF-mediated phosphorylation ofARHGAP35/p190RhoGAP, which promotes association withRASA1/p120RasGAP, inactivating RhoA while activating RAS EGFstimulation resulted in phosphorylation of PNX/Paxillin by PTK6and activation of RAC1 via CRK/CrKII, thereby promoting migrationand invasion PTK6 activates STAT3 and STAT5B to promoteproliferation Nuclear PTK6 may be important for regulating growthin normal epithelia, while cytoplasmic PTK6 might activateoncogenic signaling pathways Isoform 2 inhibits PTK6 phosphorylation and PTK6association with other tyrosine-phosphorylated proteins
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Protein Sequence
MVSRDQAHLGPKYVGLWDFKSRTDEELSFRAGDVFHVARKEEQWWWATLLDEAGGAVAQGYVPHNYLAERETVESEPWFF GCISRSEAVRRLQAEGNATGAFLIRVSEKPSADYVLSVRDTQAVRHYKIWRRAGGRLHLNEAVSFLSLPELVNYHRAQSL SHGLRLAAPCRKHEPEPLPHWDDWERPREEFTLCRKLGSGYFGEVFEGLWKDRVQVAIKVISRDNLLHQQMLQSEIQAMK KLRHKHILALYAVVSVGDPVYIITELMAKGSLLELLRDSDEKVLPVSELLDIAWQVAEGMCYLESQNYIHRDLAARNILV GENTLCKVGDFGLARLIKEDVYLSHDHNIPYKWTAPEALSRGHYSTKSDVWSFGILLHEMFSRGQVPYPGMSNHEAFLRV DAGYRMPCPLECPPSVHKLMLTCWCRDPEQRPCFKALRERLSSFTSYENPT

Motif information from Eukaryotic Linear Motif atlas (ELM)

Gene Ontology (P: Process; F: Function and C: Component terms)

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21.	During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). These two CKIs are degraded in late G1 phase by the ubiquitin pathway (Pagano et al., 1995; Bloom et al., 2003) involving the ubiquitin ligase SCF(Skp2) (Tsvetkov et al., 1999; Carrano et al., 1999; Sutterluty et al., 1999, Bornstein et al., 2003) and the cell-cycle regulatory protein Cks1 (Ganoth et al., 2001; Spruck et al 2001; Bornstein et al., 2003). Recognition of p27 by SCF(Skp2) and its subsequent ubiquitination is dependent upon Cyclin E/A:Cdk2- mediated phosphorylation at Thr 187 of p27 (Montagnoli et al., 1999). There is evidence that Cyclin A/B:Cdk1 complexes can also bind and phosphorylate p27 on Th187 (Nakayama et al., 2004). Degradation of polyubiquitinated p27 by the 26S proteasome promotes the activity of CDKs in driving cells into S phase. (Montagnoli et al., 1999; Tsvetkov et al., 1999, Carrano et al 1999). The mechanism of SCF(Skp2)-mediated degradation of p21 is similar to that of p27 in terms of its requirements for the presence of Cks1 and of Cdk2/cyclin E/A (Bornstein et al.,2003; Wang et al., 2005). In addition, as observed for p27, p21 phosphorylation at a specific site (Ser130) stimulates its ubiquitination. In contrast to p27, however, ubiquitination of p21 can take place in the absence of phosphorylation, although with less efficiency (Bornstein et al.,2003). SCF(Skp2)-mediated degradation of p27/p21 continues from late G1 through M-phase. During G0 and from early G1 to G1/S, Skp2 is degraded by the anaphase promoting complex/Cyclosome and its activator Cdh1 [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination Skp2 and, thus, plays a critical role in controlling the G1/S transition. APC/C(Cdh1) becomes active in late M-phase by the association of unphosphorylated Cdh1 with the APC/C. APC/C(Cdh1) remains active until the G1/S phase at which time it interacts with the inhibitory protein, Emi1 (Hsu et al., 2002). Inhibition of APC/C(Cdh1) activity results in an accumulation of cyclins, which leads to the phosphorylation and consequently to a further inactivation of Cdh1 at G1/S (Lukas et al., 1999). Finally, to make the inactivation of APC/C(Cdh1) permanent, Cdh1 and its E2, namely Ubc10, are eliminated in an auto-ubiquitination event (Listovsky et al., 2004; Rape and Kirschner, 2004). At G1/S, Skp2 reaccumulates as Cdh1 is inactivated, thus allowing the ubiquitination of p21 and p27 and resulting in a further increase in CDK activity
R-HSA-69231	Cyclin D associated events in G1.	Three D-type cyclins are essential for progression from G1 to S-phase. These D cyclins bind to and activate both CDK4 and CDK6. The formation of all possible complexes between the D-type cyclins and CDK4/6 is promoted by the proteins, p21(CIP1/WAF1) and p27(KIP1). The cyclin-dependent kinases are then activated due to phosphorylation by CAK. The cyclin dependent kinases phosphorylate the RB1 protein and RB1-related proteins p107 (RBL1) and p130 (RBL2). Phosphorylation of RB1 leads to release of activating E2F transcription factors (E2F1, E2F2 and E2F3). After repressor E2Fs (E2F4 and E2F5) dissociate from phosphorylated RBL1 and RBL2, activating E2Fs bind to E2F promoter sites, stimulating transcription of cell cycle genes, which then results in proper G1/S transition. The binding and sequestration of p27Kip may also contribute to the activation of CDK2 cyclin E/CDK2 cyclin A complexes at the G1/S transition (Yew et al., 2001)
R-HSA-8847993	ERBB2 Activates PTK6 Signaling.	PTK6 (BRK) is activated downstream of ERBB2 (HER) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). However, it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2, since it is known that ERBB2 forms heterodimers with EGFR (Spivak-Kroizman et al. 1992), and MET can heterodimerize with both EGFR and ERBB2 (Tanizaki et al. 2011)
R-HSA-8849468	PTK6 Regulates Proteins Involved in RNA Processing.	PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known
R-HSA-8849469	PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.	PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by other receptor tyrosine kinases (RTKs), such as IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000). PTK6 affects AKT1 activation (Zhang et al. 2005, Zheng et al. 2010) and targets negative regulator of RTKs, DOK1, for degradation (Miah et al. 2014)
R-HSA-8849470	PTK6 Regulates Cell Cycle.	PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015). PTK6 also negatively modulates CDKN1B expression via regulation of the activity of the FOXO3 (FOXO3A) transcription factor (Chan and Nimnual 2010)
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.	PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008). PTK6 inhibits RAS GTPase activating protein RASA1 (Shen et al. 2008) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al
R-HSA-8849472	PTK6 Down-Regulation.	The kinase activity of PTK6 is negatively regulated by both PTPN1 phosphatase (Fan et al. 2013), which dephosphorylates tyrosine Y342 of PTK6, and SRMS kinase (Fan et al. 2015), which phosphorylates PTK6 on tyrosine residue Y447
R-HSA-8849473	PTK6 Expression.	Levels of PTK6 increase under hypoxic conditions due to direct transcriptional regulation of PTK6 gene by hypoxia inducible transcription factors (HIFs) (Regan Anderson et al. 2013). PTK6 protein levels are also rapidly stabilized in hypoxic conditions in a HIF-independent manner (Pires et al. 2014). It has also been shown that PTK6 is ubiquitinated in normoxic conditions by a so far unknown E3 ligase (Pires et al. 2014)
R-HSA-8849474	PTK6 Activates STAT3.	PTK6-mediated phosphorylation activates STAT3 transcription factor via STAP2 adapter protein. STAT3 transcriptional target SOCS3 is a negative regulator of PTK6 and inhibits PTK6-mediated phosphorylation of STAT3, thus creating a negative feedback loop (Liu et al. 2006, Ikeda et al. 2009, Ikeda et al. 2010). PTK6 may also activate STAT5-mediated transcription (Ikeda et al. 2011)
R-HSA-8857538	PTK6 promotes HIF1A stabilization.	HBEGF-stimulated formation of EGFR heterodimers with GPNMB triggers PTK6-mediated phosphorylation and stabilization of the hypoxia inducible factor 1 alpha (HIF1A) under normoxic conditions. This process depends on the presence of a long non-coding RNA LINC01139 (LINK-A) (Lin et al. 2016)