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Fan Liu, Yan Chen, Gu Zhu, Pirro G Hysi, Sijie Wu, Kaustubh Adhikari, Krystal Breslin, Ewelina Pospiech, Merel A Hamer, Fuduan Peng, Charanya Muralidharan, Victor Acuna-Alonzo, Samuel Canizales-Quinteros, Gabriel Bedoya, Carla Gallo, Giovanni Poletti, Francisco Rothhammer, Maria Catira Bortolini, Rolando Gonzalez-Jose, Changqing Zeng, Shuhua Xu, Li Jin, André G Uitterlinden, M Arfan Ikram, Cornelia M van Duijn, Tamar Nijsten, Susan Walsh, Wojciech Branicki, Sijia Wang, Andrés Ruiz-Linares, Timothy D Spector, Nicholas G Martin, Sarah E Medland, Manfred Kayser
Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21...
February 1, 2018: Human Molecular Genetics
Koichi Ito, Sun Hee Park, Igor Katsyv, Weijia Zhang, Carmine De Angelis, Rachel Schiff, Hanna Y Irie
The non-receptor tyrosine kinase, PTK6/BRK, is highly expressed in multiple tumor types, including prostate, ovarian, and breast cancers, and regulates oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of HER2+ breast cancer. Although PTK6 is highly expressed in ER+ Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. In this study, we investigated the functions of PTK6 in ER+ Luminal breast cancer cells, including those that are relatively resistant to estrogen deprivation or targeted endocrine therapies used in the treatment of ER+ cancers...
2017: NPJ Breast Cancer
Xue-Lian Xu, Yun-Lin Ye, Zhi-Ming Wu, Qiu-Ming He, Lei Tan, Kang-Hua Xiao, Rui-Yan Wu, Yan Yu, Jia Mai, Zhi-Ling Li, Xiao-Dan Peng, Yun Huang, Xuan Li, Hai-Liang Zhang, Xiao-Feng Zhu, Zi-Ke Qin
Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase and works as an oncogene in various cancers. Recently, PTK6 has been used as a therapeutic target for breast cancer patients in a clinical study. However, the prognostic value of PTK6 in bladder cancer (BC) remains vague. Therefore, we retrieved 3 independent investigations of Oncomine database and found that PTK6 is highly expressed in BC tissues compared with corresponding normal controls. Similar results were also observed in clinical specimens at both mRNA and protein levels...
2017: Journal of Cancer
Darren J Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L Zenner, Wenjun Bie, Angela L Tyner
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342...
November 15, 2017: Nature Communications
Hyun Jae Shim, Han Ie Kim, Seung-Taek Lee
Protein tyrosine kinase (PTK)6, also known as breast tumor kinase, is a non-receptor tyrosine kinase. It is closely associated with, but evolutionarily distinct from, the Src family members. PTK6 has a role in proliferation, migration and invasion in various cancers, and therefore has been suggested as a potentially valuable therapeutic target. In an attempt to develop PTK6 inhibitors, chemicals known to inhibit various kinases were screened for their ability to inhibit PTK6. Pyrazolopyrimidine (PP)1, PP2 and a lymphocyte-specific protein tyrosine kinase inhibitor strongly inhibited the catalytic activity of PTK6 in vitro...
March 2017: Oncology Letters
Sandra Jernström, Vesa Hongisto, Suvi-Katri Leivonen, Eldri Undlien Due, Dagim Shiferaw Tadele, Henrik Edgren, Olli Kallioniemi, Merja Perälä, Gunhild Mari Mælandsmo, Kristine Kleivi Sahlberg
BACKGROUND: Approximately 15%-20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies. MATERIALS AND METHODS: Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought...
2017: Breast Cancer: Targets and Therapy
Won-Sik Shin, Hyun Jae Shim, Young Hun Lee, Minju Pyo, Jun Sang Park, So Yun Ahn, Seung-Taek Lee
Protein tyrosine kinase 6 (PTK6; also known as Brk) is closely related to the Src family kinases, but lacks a membrane-targeting myristoylation signal. Sublocalization of PTK6 at the plasma membrane enhances its oncogenic potential. To understand the mechanism(s) underlying the oncogenic property of plasma---membrane-associated PTK6, proteins phosphorylated by membrane-targeted myristoylated PTK6 (Myr-PTK6) were enriched and analyzed using a proteomics approach. Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells...
September 2017: Journal of Cellular Biochemistry
Yuichi Abe, Maiko Nagano, Asa Tada, Jun Adachi, Takeshi Tomonaga
Phosphorylation is a major post-translational modification that regulates protein function, with phosphotyrosine (pY) modifications being implicated in oncogenesis. However, global profiling of pY statuses without treatment with a tyrosine phosphatase inhibitor such as pervanadate is still challenging due to the low occupancy of pY sites. In this study, we greatly improved the identification of pY sites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) by optimization of both the pY-immunoprecipitation (pY-IP) protocol and the LC-MS/MS parameters...
February 3, 2017: Journal of Proteome Research
Manish Kumar Thakur, Swarnakumari Birudukota, Srinivasan Swaminathan, Sivarama Krishna Battula, Sarvanan Vadivelu, Rajiv Tyagi, Ramachandraiah Gosu
Human Protein tyrosine kinase 6 (PTK6)(EC:, also known as the breast tumor kinase (BRK), is an intracellular non-receptor Src-related tyrosine kinase expressed five-fold or more in human breast tumors and breast cancer cell lines but its expression being low or completely absent from normal mammary gland. There is a recent interest in targeting PTK6-positive breast cancer by developing small molecule inhibitor against PTK6. Novel imidazo[1,2-a]pyrazin-8-amines (IPA) derivative compounds and FDA approved drug, Dasatinib are reported to inhibit PTK6 kinase activity with IC50 in nM range...
January 22, 2017: Biochemical and Biophysical Research Communications
Xiaohong Chen, Bo Song, Yuanlong Lin, Lijun Cao, Shiyan Feng, Lin Zhang, Fuxiang Wang
Protein tyrosine kinase 6 (PTK6) is a nonreceptor tyrosine kinase that plays a crucial role in some tumors. However, the role of PTK6 is still unknown in hepatocellular carcinoma (HCC). In this study, we demonstrated that the PTK6 expression was upregulated in HCC tissues compared with adjacent normal tissues. Moreover, PTK6 was upregulated in the HCC cell lines (Bel7402, Hep3B, SMMC7721 and HepG2) compared with the normal liver epithelial cell line (THLE3). Ectopic expression of PTK6 promoted SMMC7721 cell proliferation, colony formation and invasion...
2016: American Journal of Translational Research
Jie Jiang, Fu Gui, Zhixiang He, Li Li, Yunzhan Li, Shunying Li, Xinrui Wu, Zhou Deng, Xihuan Sun, Xiaoxing Huang, Wei Huang, Shang Han, Ting Zhang, Zheng Wang, Bo Jiao, Siyang Song, Hongrui Wang, Lanfen Chen, Dawang Zhou, Qiang Liu, Ruibao Ren, Jianming Zhang, Xianming Deng
Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells...
January 1, 2017: Cancer Research
Ippei Kikuchi, Atsushi Takahashi-Kanemitsu, Natsuki Sakiyama, Chao Tang, Pei-Jung Tang, Saori Noda, Kazuki Nakao, Hidetoshi Kassai, Toshiro Sato, Atsu Aiba, Masanori Hatakeyama
Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes...
September 21, 2016: Nature Communications
Nancy Lévesque, Karen E Christensen, Lauren Van Der Kraak, Ana F Best, Liyuan Deng, Don Caldwell, Amanda J MacFarlane, Nicole Beauchemin, Rima Rozen
The common R653Q variant (∼20% homozygosity in Caucasians) in the synthetase domain of the folate-metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1-synthetase deficiency (Mthfd1S(+/-) ) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S(+/-) mice...
March 2017: Molecular Carcinogenesis
Xiao-Jing Wang, Ying Xiong, Ze-Biao Ma, Jian-Chuan Xia, Yan-Fang Li
BACKGROUND: Protein tyrosine kinase 6 (PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis. However, PTK6 expression status and its role in cervical squamous cell cancer are unknown. This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen, early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues...
June 16, 2016: Chinese Journal of Cancer
Koichi Ito, Sun Hee Park, Anupma Nayak, Jessica H Byerly, Hanna Y Irie
Patients with triple-negative breast cancers (TNBC) are at high risk for recurrent or metastatic disease despite standard treatment, underscoring the need for novel therapeutic targets and strategies. Here we report that protein tyrosine kinase 6 (PTK6) is expressed in approximately 70% of TNBCs where it acts to promote survival and metastatic lung colonization. PTK6 downregulation in mesenchymal TNBC cells suppressed migration and three-dimensional culture growth, and enhanced anoikis, resistance to which is considered a prerequisite for metastasis...
August 1, 2016: Cancer Research
Ricci J Haines, Richard S Beard, Rebecca A Eitner, Liwei Chen, Mack H Wu
Since inflammatory bowel diseases (IBD) represent significant morbidity and mortality in the US, the need for defining novel drug targets and inflammatory mechanisms would be of considerable benefit. Although protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) has been primarily studied in an oncogenic context, it was noted that PTK6 null mice exhibited significantly enhanced colonic epithelial barrier function. Considering that the inflammatory functions of PTK6 have not yet been explored, we hypothesized that cytokines responsible for mediating IBD, such as TNFα/IFNγ, may solicit the action of PTK6 to alter barrier function...
2016: PloS One
Lijun Cheng, Bryan P Schneider, Lang Li
BACKGROUND: Cancer has been extensively characterized on the basis of genomics. The integration of genetic information about cancers with data on how the cancers respond to target based therapy to help to optimum cancer treatment. OBJECTIVE: The increasing usage of sequencing technology in cancer research and clinical practice has enormously advanced our understanding of cancer mechanisms. The cancer precision medicine is becoming a reality. Although off-label drug usage is a common practice in treating cancer, it suffers from the lack of knowledge base for proper cancer drug selections...
July 2016: Journal of the American Medical Informatics Association: JAMIA
Priya S Mathur, Jessica J Gierut, Grace Guzman, Hui Xie, Rosa M Xicola, Xavier Llor, Michael I Chastkofsky, Ansu O Perekatt, Angela L Tyner
UNLABELLED: Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6-null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth, was examined in human colon tumor cell lines with knockdown or overexpression of PTK6...
June 2016: Molecular Cancer Research: MCR
Tarah M Regan Anderson, Shi Hong Ma, Ganesh V Raj, John A Cidlowski, Taylor M Helle, Todd P Knutson, Raisa I Krutilina, Tiffany N Seagroves, Carol A Lange
Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent...
March 15, 2016: Cancer Research
Feifei Zhang, Yuhao Luo, Ziyun Shao, Lijun Xu, Xiaoxu Liu, Ya Niu, Jiaolong Shi, Xuegang Sun, Yawei Liu, Yanqing Ding, Liang Zhao
Constitutive overactivation of TGFβ signaling is a common event in human cancer progression and acts as a major inducer of epithelial-mesenchymal transition (EMT). In pre-metastatic colorectal cancer (CRC) cells, however, this cascade is tightly controlled and the underlying mechanism in TGFβ stimulated hyperactivation of downstream Smad pathway remains elusive. In this study, expression of miR-187 was downregulated in colorectal cancer (CRC) compared with adjacent normal tissues. miR-187 could suppress the formation of aggressive phenotype in CRC and inactivate Smad pathway, thus preventing EMT...
April 10, 2016: Cancer Letters
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