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Differential requirement of EGF receptor and its tyrosine kinase for AP-1 transactivation induced by EGF and TPA

Oncogene volume 22, pages 211–219 (2003)Cite this article

Abstract

The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including cell differentiation, proliferation, apoptosis and oncogenic transformation. It is thought that the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced AP-1 activity is because of the activation of the PKC/MAPK/AP-1 pathway, although the detailed molecular mechanism has not been fully characterized. The tyrosine kinases of epidermal growth factor receptor (EGFR) lie at the head of a complex of signal transduction cascade that modulates cell proliferation, survival, adhesion, migration and differentiation. Currently, little is known about whether EGFR or its tyrosine kinase is necessary for TPA-induced AP-1 activation. In the present study, we investigated this issue using a well-characterized mouse fibroblast B82 cell line, which is devoid of the EGFR, and its stable transfectants with either wild-type EGFR (B82L) or tyrosine kinase-deficient EGFR (mutation at Lys-721) (B82M721). We demonstrated that the TPA or epidermal growth factor (EGF) induced AP-1 activation in the B82L cells that express wild-type EGFR, but not in the B82 cell, whereas autophosphorylation at tyrosine1173 of EGFR in B82L cells was only induced by EGF, but not TPA. The expression of tyrosine kinase-deficient EGFR (mutation at Lys-721) (B82M721) resulted in deficiency of AP-1 induction in cellular response to EGF, while TPA treatment led to fully AP-1 activation. Furthermore, the mutation at Lys-721 of EGFR resulted in impairing of EGFR autophosphorylation at tyrosine1173 induced by EGF. Based on these results, we conclude that TPA-induced AP-1 activation requires the basal level-EGFR protein, but not EGFR tyrosine kinase and EGFR autophosphorylation at tyrosine1173, whereas both EGFR tyrosine kinase and EGFR autophosphorylation at Y1173 play a critical role in EGF-induced AP-1 activation.

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Abbreviations

AP-1:

activator protein-1

ERKs:

extracellular signal-regulated protein kinases

MAPKs:

mitogen-activated protein kinases

JNKs:

c-Jun N-terminal kinases

TPA:

12-O-tetradecanoylphorbol-13-acetate

EGF:

epidermal growth factor

FBS:

fet al bovine serum

MEM:

minimal essential medium

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Acknowledgements

This work was supported in part by NIH grant numbers ES 00260 and CA 16087.

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Author notes

  1. Yi Huang: Summer student from Monroe–Woodbury High School, 155 Dunderberg Road. Central Valley, NY 10917, USA

Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, 10987, NY, USA

    Jingxia Li, Yi Huang & Chuanshu Huang

  2. Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, 26506, WV, USA

    Cuiling Ma, Yi Huang & Jia Luo

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  1. Jingxia Li
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Correspondence to Chuanshu Huang.

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Li, J., Ma, C., Huang, Y. et al. Differential requirement of EGF receptor and its tyrosine kinase for AP-1 transactivation induced by EGF and TPA. Oncogene 22, 211–219 (2003). https://doi.org/10.1038/sj.onc.1206102

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