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Differential expression of FAK and Pyk2 in metastatic and non-metastatic EL4 lymphoma cell lines

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Abstract

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12-myristate 13-acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk-mediated growth arrest. In resistant cells, PMA induces a low level of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant cells are more adherent to culture substrate than are sensitive cells. In this study, the roles of the protein tyrosine kinases FAK and Pyk2 in EL4 phenotype were examined, with a particular emphasis on the role of these proteins in metastasis. FAK is expressed only in PMA-resistant (or intermediate phenotype) EL4 cells, correlating with enhanced cell–substrate adherence, while Pyk2 is more highly expressed in non-adherent PMA-sensitive cells. PMA treatment causes modulation of mRNA for FAK (up-regulation) and Pyk2 (down-regulation) in PMA-sensitive but not PMA-resistant EL4 cells. The increase in Pyk2 mRNA is correlated with an increase in Pyk2 protein expression. The roles of FAK in cell phenotype were further explored using transfection and knockdown experiments. The results showed that FAK does not play a major role in modulating PMA-induced Erk activation in EL4 cells. However, the knockdown studies demonstrated that FAK expression is required for proliferation and migration of PMA-resistant cells. In an experimental metastasis model using syngeneic mice, only FAK-expressing (PMA-resistant) EL4 cells form liver tumors. Taken together, these studies suggest that FAK expression promotes metastasis of EL4 lymphoma cells.

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Abbreviations

EGF:

Epidermal growth factor

FAK:

Focal adhesion kinase

PMA:

Phorbol 12-myristate 13-acetate

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Acknowledgments

This work was supported by the National Institutes of Health (CA58640 and CA94144), National Science Foundation (EPS-9630167), U.S. Department of Defense (DAMD17-98-8524 and DAMD17-01-1-0730), the University Research Committee of the Medical University of South Carolina, and the Medical Scientist Training Program at the Medical University of South Carolina. We thank David Morris for supplying EL4 cells, Steven Hanks for supplying the FAK expression vector, David Cole for the Pyk2 expression vector, April Wisehart-Johnson for technical assistance, and Derek J. Pouchnik for assistance with the microarray analysis performed in the core facility supported by the Center for Biotechnology at WSU.

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Authors and Affiliations

  1. Program in Nutrition and Exercise Physiology, Washington State University, Spokane, WA, 99210-1495, USA

    Zhihong Zhang & Kathryn E. Meier

  2. Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, 99164, USA

    Manpreet S. Chahal

  3. Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Stewart M. Knoepp, Hsun Ku, Heather M. Sansbury & Yuhuan Xie

  4. Department of Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Stephen Tomlinson

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  1. Zhihong Zhang
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Correspondence to Kathryn E. Meier.

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Zhang, Z., Knoepp, S.M., Ku, H. et al. Differential expression of FAK and Pyk2 in metastatic and non-metastatic EL4 lymphoma cell lines. Clin Exp Metastasis 28, 551–565 (2011). https://doi.org/10.1007/s10585-011-9391-y

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