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Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation

Oncogene volume 21, pages 8817–8829 (2002)Cite this article

Abstract

Etk/Bmx, a member of the Tec family of non-receptor tyrosine kinase, is characterized by an N-terminal PH domain and has recently been shown to be involved in the regulation of various cellular processes, including proliferation, differentiation, motility and apoptosis. Since VEGF and the activation of its signaling pathway have been implicated in modulating a variety of biological responses, we characterized the role of Etk-dependent signaling pathways involved in the upregulation of VEGF expression, and explored the functional implications of this enhancement in sustaining cell proliferation and survival. Using Northern and Western analyses, transient transfections, and pharmacological agents, we demonstrate that Etk activation alone is sufficient to transcriptionally induce VEGF expression, independent of the previously identified hypoxia response element (HRE), in both Pa-4 epithelial and TR-BBB endothelial cells under normoxia. In addition, Etk utilizes both MEK/ERK and PI3-K/Pak1 signaling pathways in concert to activate VEGF transcription. Functionally, Etk activation elicits a profound stimulatory effect on TR-BBB cell proliferation and formation of capillary-like networks in Matrigel containing reduced levels of growth factors. Finally, antisense oligonucleotides against either endogenous VEGF or Etk abrogate the proliferation of Etk-activated TR-BBB cells, and exogenous VEGF treatment stimulates endogenous Etk tyrosine phosphorylation in HUVECs. Taken together, these results indicate that VEGF is both an Etk downstream target gene and an Etk upstream activator, constituting a reciprocal Etk-VEGF autoregulatory loop. These findings, to our knowledge, are the first delineation of a network of positive feedforward signaling pathways that converge on the Etk-VEGF axis, causally associating Etk-mediation of VEGF induction with enhanced cellular processes in both epithelial and endothelial cells.

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Acknowledgements

We thank Drs Rizwan Masood, Parkash Gill, Yun Qiu and Gary Bokoch for useful reagents and Dr Wei-Chiang Shen for helpful suggestions on the Matrigel assay. This work was supported in part by National Institute of Health Research grants R01 DE 10742 and R01 DE 14183 (to DK Ann), R01 HL 38658 and R01 HL 64365 (to K-J Kim), and Predoctoral Fellowship DE 07211 (to CH Chau).

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, 90033, California, CA, USA

    Cindy H Chau, Hong-Tao Deng, Kwang-Jin Kim & David K Ann

  2. Department of Medicine, University of Southern California, Los Angeles, 90033, California, CA, USA

    Kwang-Jin Kim

  3. Department of Physiology and Biophysics, University of Southern California, Los Angeles, 90033, California, CA, USA

    Kwang-Jin Kim

  4. Department of Biomedical Engineering, University of Southern California, Los Angeles, 90033, California, CA, USA

    Kwang-Jin Kim

  5. Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, 90033, California, CA, USA

    Kwang-Jin Kim

  6. Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, 90033, California, CA, USA

    David K Ann

  7. Division of Molecular and Genomic Medicine, National Health Research Institute, Taipei, 11529, Taiwan

    Kai-Yun Chen & Hsiu-Ming Shih

  8. Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, 930-0194, Japan

    Ken-ichi Hosoya

  9. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    Tetsuya Terasaki

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  1. Cindy H Chau
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Correspondence to David K Ann.

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Chau, C., Chen, KY., Deng, HT. et al. Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation. Oncogene 21, 8817–8829 (2002). https://doi.org/10.1038/sj.onc.1206032

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  • DOI: https://doi.org/10.1038/sj.onc.1206032

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