Proteopedia

6cz2

Structure of the PTK6 kinase domainStructure of the PTK6 kinase domain

Structural highlights

6cz2 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Protein tyrosine kinase 6 (PTK6, or BRK) is aberrantly expressed in breast cancers, and emerging as an oncogene that promotes tumor cell proliferation, migration and evasion. Both kinase-dependent and -independent functions of PTK6 in driving tumor growth have been described, therefore targeting PTK6 kinase activity by small molecule inhibitors as a therapeutic approach to treat cancers remains to be validated. In this study, we identified novel, potent and selective PTK6 kinase inhibitors as a means to investigate the role of PTK6 kinase activity in breast tumorigenesis. We report here the crystal structures of apo-PTK6 and inhibitor-bound PTK6 complexes, providing the structural basis for small molecule interaction with PTK6. The kinase inhibitors moderately suppress tumor cell growth in 2D and 3D cell cultures. However, the tumor cell growth inhibition shows neither correlation with the PTK6 kinase activity inhibition, nor the total or activated PTK6 protein levels in tumor cells, suggesting that the tumor cell growth is independent of PTK6 kinase activity. Furthermore, in engineered breast tumor cells overexpressing PTK6, the inhibition of PTK6 kinase activity does not parallel the inhibition of tumor cell growth with a >500-fold shift in compound potencies (IC50 values). Overall, these findings suggest that the kinase activity of PTK6 does not play a significant role in tumorigenesis, thus providing important evidence against PTK6 kinase as a potential therapeutic target for breast cancer treatment.

Small molecule inhibitors reveal PTK6 kinase is not an oncogenic driver in breast cancers.,Qiu L, Levine K, Gajiwala KS, Cronin CN, Nagata A, Johnson E, Kraus M, Tatlock J, Kania R, Foley T, Sun S PLoS One. 2018 Jun 7;13(6):e0198374. doi: 10.1371/journal.pone.0198374., eCollection 2018. PMID:29879184[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ Qiu L, Levine K, Gajiwala KS, Cronin CN, Nagata A, Johnson E, Kraus M, Tatlock J, Kania R, Foley T, Sun S. Small molecule inhibitors reveal PTK6 kinase is not an oncogenic driver in breast cancers. PLoS One. 2018 Jun 7;13(6):e0198374. doi: 10.1371/journal.pone.0198374., eCollection 2018. PMID:29879184 doi:http://dx.doi.org/10.1371/journal.pone.0198374

6cz2, resolution 2.50Å

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