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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, Hong-Rui Wang, Lanfen Chen, Dawang Zhou, Qiang Liu, Ruibao Ren, Jianming Zhang, Xianming Deng
Approximately 80% of breast cancers overexpress the kinase BRK/PTK6, 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 employed 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...
October 10, 2016: 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...
September 6, 2016: 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...
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
Andrea F N Rosenberger, Riet Hilhorst, Elisabeth Coart, Leandro García Barrado, Faris Naji, Annemieke J M Rozemuller, Wiesje M van der Flier, Philip Scheltens, Jeroen J M Hoozemans, Saskia M van der Vies
Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform...
2015: Journal of Alzheimer's Disease: JAD
M Peng, S M Ball-Kell, A L Tyner
Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6-/- mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation...
2015: Cell Death & Disease
Sun Hee Park, Koichi Ito, William Olcott, Igor Katsyv, Gwyneth Halstead-Nussloch, Hanna Y Irie
INTRODUCTION: Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2(+) (Her2(+)) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibition is an effective strategy to inhibit growth and survival of Her2(+) breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2(+) breast cancer, either intrinsically or acquired after continuous drug exposure...
2015: Breast Cancer Research: BCR
Prasanna Abeyrathna, Yunchao Su
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1...
November 2015: Vascular Pharmacology
Hiroaki Ono, Marc D Basson, Hiromichi Ito
UNLABELLED: Protein Tyrosine Kinase 6 (PTK6) is a non-receptor-type tyrosine kinase known to be expressed in various cancers, including pancreatic cancer. The role of PTK6 in cancer chemoresistance remains unclear. Therefore, it was hypothesized that PTK6 mechanistically regulates gemcitabine resistance in pancreatic cancer. Gemcitabine treatment stimulated endogenous PTK6 overexpression in MIAPaCa2 and Panc1 cells. PTK6 gene silencing increased cell survival after gemcitabine treatment and decreased apoptosis, whereas PTK6 overexpression decreased cell survival and increased apoptosis...
August 2015: Molecular Cancer Research: MCR
Tiffany Tsui, W Todd Miller
Brk (breast tumor kinase, also known as PTK6) is a nonreceptor tyrosine kinase that is aberrantly expressed in several cancers and promotes cell proliferation and transformation. Genome sequencing studies have revealed a number of cancer-associated somatic mutations in the Brk gene; however, their effect on Brk activity has not been examined. We analyzed a panel of cancer-associated mutations and determined that several of the mutations activate Brk, while two eliminated enzymatic activity. Three of the mutations (L16F, R131L, and P450L) are located in important regulatory domains of Brk (the SH3, SH2 domains, and C-terminal tail, respectively)...
May 26, 2015: Biochemistry
Michael I Chastkofsky, Wenjun Bie, Susan M Ball-Kell, Yu-Ying He, Angela L Tyner
Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the epithelial linings of the gastrointestinal tract and the skin, where it is expressed in nondividing differentiated cells. We found that PTK6 expression increases in the epidermis following UVB treatment. To evaluate the roles of PTK6 in the skin following UVB-induced damage, we exposed back skin of Ptk6 +/+ and Ptk6 -/- SENCAR mice to incremental doses of UVB for 30 weeks. Wild-type mice were more sensitive to UVB and exhibited increased inflammation and greater activation of signal transducer and activator of transcription-3 (STAT3) than Ptk6-/- mice...
October 2015: Journal of Investigative Dermatology
Sara Kiflemariam, Viktor Ljungström, Fredrik Pontén, Tobias Sjöblom
The tyrosine kinome and phosphatome harbor oncogenes and tumor suppressor genes and important regulators of angiogenesis and tumor stroma formation. To provide a better understanding of their potential roles in cancer, we analyzed the expression of 85 tyrosine kinases and 42 tyrosine phosphatases by in situ hybridization 48 human normal and 24 tumor tissue specimens. Nine-tenths of the assessed transcripts had tumor cell expression concordant with expression array databases. Further, pan-cancer expression of AATK, PTPRK, and PTPRU and expression of PTPRS in a subset of tumors were observed...
June 2015: American Journal of Pathology
Pankaj Jha, Dongsheng Lu, Yuan Yuan, Shuhua Xu
Analysis of natural selection events is an attractive strategy for identification of functional variants shaped by gene-environmental interactions and human adaptation. Here, we identified PTK6, a Src-related tyrosine kinase gene, underlying positive selection in East Asian populations. Interestingly, PTK6 variant showed significant correlation with gastric cancer incidences which was the highest in East Asian populations. The high prevalence of gastric cancer in East Asians was also believed to be strongly affected by Helicobacter pylori infection and dietary habit...
October 2015: Molecular Genetics and Genomics: MGG
Yoshiaki Mizuguchi, Susan Specht, Kumiko Isse, Eizaburo Sasatomi, John G Lunz, Toshihiro Takizawa, Anthony J Demetris
BACKGROUND & AIMS: Breast tumor kinase (BRK) augments proliferation and promotes cell survival in breast cancers via interactions with SH2 and SH3 ligand-containing proteins, such as receptor tyrosine kinases (RTK; e.g. EGFR, ErbB2/neu). Since RTK contribute to cholangiocarcinoma (CC) evolution we probed BRK protein expression and function in normal and CC livers. METHODS: Immunohistochemical staining of normal livers and CC (n=93) in a tissue microarray and three CC and an immortalized human cholangiocyte cell lines (real-time PCR, Western blotting, siRNA) were used to study the functional relationships between BRK, EGFR, ErbB2, SAM68, and SPRR2a...
August 2015: Journal of Hepatology
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