| Structural highlights
Function
[PTK6_HUMAN] 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.[10] [11] [12] [13] [14] [15] [16] [17] [18]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumors. To understand the structural basis of PTK6 function, we have determined the solution structure and backbone dynamics of the PTK6-Src homology 2 (SH2) domain using multidimensional NMR spectroscopy. The solution structure clearly indicates that the SH2 domain of human PTK6 contains a consensus alpha/beta-fold and a Tyr(P) peptide binding surface, which are common to other SH2 domains. However, two of the alpha-helices (alphaA and alphaB) are located on opposite faces of the central beta-sheet. In addition, the topological arrangement of a central four-stranded antiparallel beta-sheet (strands betaA, betaB, betaC, and betaD) differs from that of other Src family members. Backbone dynamics and Tyr(P) peptide titration experiments revealed that the putative ligand binding sites of the PTK6-SH2 domain undergo distinctive internal motions when compared with other regions of the protein. Surface plasmon resonance analysis showed that the Tyr(P) peptide had a dissociation constant of about 60 microm, which is substantially weaker binding than previously reported for Src family members. The solution structure together with data from the ligand binding mode of PTK6-SH2 provides insight into the molecular basis of the autoinhibitory role of PTK6.
Solution structure and backbone dynamics of the non-receptor protein-tyrosine kinase-6 Src homology 2 domain.,Hong E, Shin J, Kim HI, Lee ST, Lee W J Biol Chem. 2004 Jul 9;279(28):29700-8. Epub 2004 Mar 31. PMID:15056653[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mitchell PJ, Sara EA, Crompton MR. A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene. 2000 Aug 31;19(37):4273-82. PMID:10980601 doi:http://dx.doi.org/10.1038/sj.onc.1203775
- ↑ Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem. 2004 Dec 24;279(52):54398-404. Epub 2004 Oct 7. PMID:15471878 doi:http://dx.doi.org/10.1074/jbc.M409579200
- ↑ Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH. Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin. Mol Cell Biol. 2004 Dec;24(24):10558-72. PMID:15572663 doi:http://dx.doi.org/10.1128/MCB.24.24.10558-10572.2004
- ↑ Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005 Jan 21;280(3):1982-91. Epub 2004 Nov 10. PMID:15539407 doi:http://dx.doi.org/10.1074/jbc.M412038200
- ↑ Lukong KE, Larocque D, Tyner AL, Richard S. Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. J Biol Chem. 2005 Nov 18;280(46):38639-47. Epub 2005 Sep 22. PMID:16179349 doi:http://dx.doi.org/10.1074/jbc.M505802200
- ↑ Liu L, Gao Y, Qiu H, Miller WT, Poli V, Reich NC. Identification of STAT3 as a specific substrate of breast tumor kinase. Oncogene. 2006 Aug 10;25(35):4904-12. Epub 2006 Mar 27. PMID:16568091 doi:http://dx.doi.org/10.1038/sj.onc.1209501
- ↑ Weaver AM, Silva CM. Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. 2007;9(6):R79. PMID:17997837 doi:http://dx.doi.org/10.1186/bcr1794
- ↑ Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH. Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res. 2008 Oct 1;68(19):7779-87. doi: 10.1158/0008-5472.CAN-08-0997. PMID:18829532 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0997
- ↑ Brauer PM, Zheng Y, Evans MD, Dominguez-Brauer C, Peehl DM, Tyner AL. The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of beta-catenin. PLoS One. 2011 Mar 30;6(3):e14789. doi: 10.1371/journal.pone.0014789. PMID:21479203 doi:http://dx.doi.org/10.1371/journal.pone.0014789
- ↑ Mitchell PJ, Sara EA, Crompton MR. A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene. 2000 Aug 31;19(37):4273-82. PMID:10980601 doi:http://dx.doi.org/10.1038/sj.onc.1203775
- ↑ Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem. 2004 Dec 24;279(52):54398-404. Epub 2004 Oct 7. PMID:15471878 doi:http://dx.doi.org/10.1074/jbc.M409579200
- ↑ Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH. Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin. Mol Cell Biol. 2004 Dec;24(24):10558-72. PMID:15572663 doi:http://dx.doi.org/10.1128/MCB.24.24.10558-10572.2004
- ↑ Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005 Jan 21;280(3):1982-91. Epub 2004 Nov 10. PMID:15539407 doi:http://dx.doi.org/10.1074/jbc.M412038200
- ↑ Lukong KE, Larocque D, Tyner AL, Richard S. Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. J Biol Chem. 2005 Nov 18;280(46):38639-47. Epub 2005 Sep 22. PMID:16179349 doi:http://dx.doi.org/10.1074/jbc.M505802200
- ↑ Liu L, Gao Y, Qiu H, Miller WT, Poli V, Reich NC. Identification of STAT3 as a specific substrate of breast tumor kinase. Oncogene. 2006 Aug 10;25(35):4904-12. Epub 2006 Mar 27. PMID:16568091 doi:http://dx.doi.org/10.1038/sj.onc.1209501
- ↑ Weaver AM, Silva CM. Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. 2007;9(6):R79. PMID:17997837 doi:http://dx.doi.org/10.1186/bcr1794
- ↑ Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH. Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res. 2008 Oct 1;68(19):7779-87. doi: 10.1158/0008-5472.CAN-08-0997. PMID:18829532 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0997
- ↑ Brauer PM, Zheng Y, Evans MD, Dominguez-Brauer C, Peehl DM, Tyner AL. The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of beta-catenin. PLoS One. 2011 Mar 30;6(3):e14789. doi: 10.1371/journal.pone.0014789. PMID:21479203 doi:http://dx.doi.org/10.1371/journal.pone.0014789
- ↑ Hong E, Shin J, Kim HI, Lee ST, Lee W. Solution structure and backbone dynamics of the non-receptor protein-tyrosine kinase-6 Src homology 2 domain. J Biol Chem. 2004 Jul 9;279(28):29700-8. Epub 2004 Mar 31. PMID:15056653 doi:10.1074/jbc.M313185200
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