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Dive into the research topics where Wenjun Bie is active.

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Featured researches published by Wenjun Bie.


Molecular and Cellular Biology | 2006

Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine

Andrea Haegebarth; Wenjun Bie; Ruyan Yang; Susan E. Crawford; Valeri Vasioukhin; Elaine Fuchs; Angela L. Tyner

ABSTRACT Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6−/− mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear β-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.


Journal of Cell Science | 2010

Identification of β-catenin as a target of the intracellular tyrosine kinase PTK6

Helena L. Palka-Hamblin; Jessica Gierut; Wenjun Bie; Patrick M. Brauer; Yu Zheng; John M. Asara; Angela L. Tyner

Disruption of the gene encoding protein tyrosine kinase 6 (PTK6) leads to increased growth, impaired enterocyte differentiation and higher levels of nuclear β-catenin in the mouse small intestine. Here, we demonstrate that PTK6 associates with nuclear and cytoplasmic β-catenin and inhibits β-catenin- and T-cell factor (TCF)-mediated transcription. PTK6 directly phosphorylates β-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64. However, mutation of these sites does not abrogate the ability of PTK6 to inhibit β-catenin transcriptional activity. Outcomes of PTK6-mediated regulation appear to be dependent on its intracellular localization. In the SW620 colorectal adenocarcinoma cell line, nuclear-targeted PTK6 negatively regulates endogenous β-catenin/TCF transcriptional activity, whereas membrane-targeted PTK6 enhances β-catenin/TCF regulated transcription. Levels of TCF4 and the transcriptional co-repressor TLE/Groucho increase in SW620 cells expressing nuclear-targeted PTK6. Knockdown of PTK6 in SW620 cells leads to increased β-catenin/TCF transcriptional activity and increased expression of β-catenin/TCF target genes Myc and Survivin. Ptk6-null BAT-GAL mice, containing a β-catenin-activated LacZ reporter transgene, have increased levels of β-galactosidase expression in the gastrointestinal tract. The ability of PTK6 to negatively regulate β-catenin/TCF transcription by modulating levels of TCF4 and TLE/Groucho could contribute to its growth-inhibitory activities in vivo.


Gastroenterology | 2009

Induction of Protein Tyrosine Kinase 6 in Mouse Intestinal Crypt Epithelial Cells Promotes DNA Damage–Induced Apoptosis

Andrea Haegebarth; Ansu O. Perekatt; Wenjun Bie; Jessica Gierut; Angela L. Tyner

BACKGROUND & AIMS Protein tyrosine kinase 6 (PTK6) is expressed in epithelial linings of the gastrointestinal tract. PTK6 sensitizes the nontransformed Rat1a fibroblast cell line to apoptotic stimuli. The aim of this study was to determine if PTK6 regulates apoptosis in vivo after DNA damage in the small intestine. METHODS Wild-type and Ptk6(-/-) mice were subjected to gamma-irradiation; intestinal tissues were collected, protein was isolated, and samples were fixed for immunohistochemical analyses at 0, 6, and 72 hours after the mice were irradiated. Expression of PTK6 was examined in the small intestine before and after irradiation. Apoptosis and proliferation were compared between wild-type and Ptk6(-/-) mice. Expression and activation of prosurvival signaling proteins were assessed. RESULTS Irradiation induced PTK6 in crypt epithelial cells of the small intestine in wild-type mice. Induction of PTK6 corresponded with DNA damage-induced apoptosis in the wild-type small intestine. Following irradiation, the apoptotic response was impaired in the intestinal crypts of Ptk6(-/-) mice. Increased activation of AKT and extracellular signal-regulated kinase (ERK)1/2 and increased inhibitory phosphorylation of the proapoptotic protein BAD were detected in Ptk6(-/-) mice after irradiation. In response to the induction of apoptosis, compensatory proliferation increased in the small intestines of wild-type mice but not in Ptk6(-/-) mice at 6 hours after irradiation. CONCLUSIONS PTK6 is a stress-induced kinase that promotes apoptosis by inhibiting prosurvival signaling. After DNA damage, induction of PTK6 is required for efficient apoptosis and inhibition of AKT and ERK1/2.


Journal of Gastroenterology and Hepatology | 2008

Conditionally immortalized colonic epithelial cell line from a Ptk6 null mouse that polarizes and differentiates in vitro

Robert H. Whitehead; Pamela S. Robinson; Janice A. Williams; Wenjun Bie; Angela L. Tyner; Jeffrey L. Franklin

Background and Aims:  PTK6 is an intracellular src‐related tyrosine kinase that regulates differentiation in the intestine, where knockout animals have increased proliferative activity and growth characteristics. To explore the phenotype further we attempted to establish epithelial cell lines from the intestinal mucosa.


Cancer Research | 2013

PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer

Yu Zheng; Zebin Wang; Wenjun Bie; Patrick M. Brauer; Bethany E. Perez White; Jing Li; Veronique Nogueira; Pradip Raychaudhuri; Nissim Hay; Debra A. Tonetti; Virgilia Macias; Andre Kajdacsy-Balla; Angela L. Tyner

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426-37. ©2013 AACR.


Gastroenterology | 2011

Disruption of the Mouse Protein Tyrosine Kinase 6 Gene Prevents STAT3 Activation and Confers Resistance to Azoxymethane

Jessica Gierut; Yu Zheng; Wenjun Bie; Robert E. Carroll; Susan Ball-Kell; Andrea Haegebarth; Angela L. Tyner

BACKGROUND & AIMS Protein tyrosine kinase 6 (PTK6) is expressed throughout the gastrointestinal tract and is a negative regulator of proliferation that promotes differentiation and DNA-damage-induced apoptosis in the small intestine. PTK6 is not expressed in normal mammary gland, but is induced in most human breast tumors. Signal transducer and activator of transcription 3 (STAT3) mediates pathogenesis of colon cancer and is a substrate of PTK6. We investigated the role of PTK6 in colon tumorigenesis. METHODS Ptk6+/+ and Ptk6-/- mice were injected with azoxymethane alone or in combination with dextran sodium sulfate; formation of aberrant crypt foci and colon tumors was examined. Effects of disruption of Ptk6 on proliferation, apoptosis, and STAT3 activation were examined by immunoblot and immunohistochemical analyses. Regulation of STAT3 activation was examined in the HCT116 colon cancer cell line and young adult mouse colon cells. RESULTS Ptk6-/- mice developed fewer azoxymethane-induced aberrant crypt foci and tumors. Induction of PTK6 increased apoptosis, proliferation, and STAT3 activation in Ptk6+/+ mice injected with azoxymethane. Disruption of Ptk6 impaired STAT3 activation following azoxymethane injection, and reduced active STAT3 levels in Ptk6-/- tumors. Stable knockdown of PTK6 reduced basal levels of active STAT3, as well as activation of STAT3 by epidermal growth factor in HCT116 cells. Disruption of Ptk6 reduced activity of STAT3 in young adult mouse colon cells. CONCLUSIONS PTK6 promotes STAT3 activation in the colon following injection of the carcinogen azoxymethane and regulates STAT3 activity in mouse colon tumors and in the HCT116 and young adult mouse colon cell lines. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice.


Cell Cycle | 2006

Differential regulation of D-type cyclins in the mouse intestine

Ruyan Yang; Wenjun Bie; Andrea Haegebarth; Angela L. Tyner

The intestinal epithelium undergoes continuous rapid renewal throughout adult life. To examine contributions of D-type cyclins to proliferation in the intestine, we examined D-type cyclin expression in the mouse proximal and distal small intestine and colon. Cyclin D1 was expressed throughout the small and large intestine. In contrast, cyclin D2 and D3 protein levels were not readily detectable in the duodenum. Levels of RNAs encoding all three D-type cyclins were higher in the ileum and colon than in the duodenum. Immunohistochemistry revealed that cyclin D1 and D2 are expressed in colonic epithelial cells, with cyclin D2 being more restricted to the proliferative zone. Expression of cyclin D1 and D2 was detected in conditionally immortalized young adult mouse colon (YAMC) cells and in a colon epithelial cell line derived from the ApcMin/+ mouse (IMCE cells), with higher basal levels of both cyclins in the IMCE cells. In an experimental model of colitis, levels of cyclin D1 mRNA increased significantly, and cyclin D1 protein was localized to both epithelial cells and inflammatory cells in the colon. The individual D-type cyclins may make different contributions to proliferation, disease and development of cancer in the intestine.


Molecular Cancer Therapeutics | 2012

Targeting Protein Tyrosine Kinase 6 Enhances Apoptosis of Colon Cancer Cells Following DNA Damage

Jessica Gierut; Priya S. Mathur; Wenjun Bie; Jin Han; Angela L. Tyner

Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that has distinct functions in normal epithelia and cancer. It is expressed primarily in nondividing epithelial cells in the normal intestine, where it promotes differentiation. However, after DNA damage, PTK6 is induced in proliferating progenitor cells, where it contributes to apoptosis. We examined links between PTK6 and the tumor suppressor p53 in the isogenic p53+/+ and p53−/− HCT116 colon tumor cell lines. We found that p53 promotes expression of PTK6 in HCT116 cells, and short hairpin RNA-mediated knockdown of PTK6 leads to reduced induction of the cyclin-dependent kinase inhibitor p21. Knockdown of PTK6 enhances apoptosis in HCT116 cells with wild-type p53, following treatment of cells with γ-radiation, doxorubicin, or 5-fluorouracil. No differences in the activation of AKT, ERK1/2, or ERK5, known PTK6-regulated prosurvival signaling proteins, were detected. However, activity of STAT3, a PTK6 substrate, was impaired in cells with knockdown of PTK6 following DNA damage. In contrast to its role in the normal epithelium following DNA damage, PTK6 promotes survival of cancer cells with wild-type p53 by promoting p21 expression and STAT3 activation. Targeting PTK6 in combination with use of chemotherapeutic drugs or radiation may enhance death of colon tumor cells with wild-type p53. Mol Cancer Ther; 11(11); 2311–20. ©2012 AACR.


Journal of Investigative Dermatology | 2015

Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin.

Michael I. Chastkofsky; Wenjun Bie; Susan 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 skin, where it is expressed in nondividing differentiated cells. We found 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 thirty weeks. Wild type mice were more sensitive to UVB and exhibited increased inflammation and greater activation of STAT3 than Ptk6−/− mice. Disruption of Ptk6 did not have an impact on proliferation, although PTK6 was expressed and activated in basal epithelial cells in wild type mice following UVB treatment. However, wild type mice exhibited shortened tumor latency and increased tumor load compared with Ptk6−/− mice, and STAT3 activation was increased in these tumors. PTK6 activation was detected in UVB-induced tumors, and this correlated with increased activating phosphorylation of FAK and BCAR1. Activation of PTK6 was also detected in human squamous cell carcinomas of the skin. Although PTK6 plays roles in normal differentiation, it also contributes to UVB induced injury and tumorigenesis in vivo.


Cancer Biology & Therapy | 2008

Functions of p21 and p27 in the Regenerating Epithelial Linings of the Mouse Small and Large Intestine

Yu Zheng; Wenjun Bie; Ruyan Yang; Ansu O. Perekatt; Aleksandra J. Poole; Angela L. Tyner

The epithelial linings of the small and large intestine are rapidly turned over and provide an ideal system for exploring links between differentiation and regulation of cell cycle exit. We utilized wild type, p21-/-, p27-/- and p21/p27-/- mice to address contributions of the Cdk inhibitors p21 and p27 to proliferation and differentiation in the mouse gastrointestinal tract. We did not detect any significant differences in proliferation, and all differentiated epithelial cell lineages were represented in all four genotypes. These data indicate that p21 and p27 do not play essential roles in the regulation of normal epithelial renewal in the intestine. These Cdk inhibitors are not needed in vivo for either assembly of Cdk/Cyclin complexes that drive active proliferation, or inhibition of Cdk/Cyclin complexes during cell cycle exit. However, expression of Cyclin D2 and to a lesser degree Cyclin D3 was reduced in p27-/- and p21/p27-/- mice, indicating a unique role for p27 in the regulation of these specific D-type Cyclins in vivo. In the absence of p27, reduced levels of Cyclin D2 and D3 may help to counteract increased proproliferative signals in the intestine.

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Angela L. Tyner

University of Illinois at Chicago

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Jessica Gierut

University of Illinois at Chicago

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Yu Zheng

University of Illinois at Chicago

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Ruyan Yang

University of Illinois at Chicago

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Andre Kajdacsy-Balla

University of Illinois at Chicago

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Ansu O. Perekatt

University of Illinois at Chicago

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Darien Heap

University of Illinois at Chicago

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Darren J. Wozniak

University of Illinois at Chicago

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Jason Derry

University of Illinois at Chicago

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