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Scaffolding protein Gab2 mediates fibroblast transformation by the SEA tyrosine kinase

Oncogene volume 22, pages 6311–6318 (2003)Cite this article

Abstract

Transformation of fibroblasts by V-SEA involves activation of the ERK and phosphatidylinositol 3-kinase (PI3K) pathways. Effector proteins that are key mediators of the ERK and PI3K pathways, namely Grb2, the tyrosine phosphatase, SHP2 and PI3K, interact with the two phosphotyrosines found in the bidentate motif in the carboxy-terminal region of V-SEA. Genetic analysis demonstrated that while Y557 was a primary binding site and thus activator of the PI3K-Akt pathway, Y564 also contributed to the activation of this pathway. Y564 was located within a Grb2-binding motif, this raised the possibility that a protein that associated with Grb2 might be important for this PI3K activation. The scaffolding proteins Gab1 and/or Gab2 were candidates for this role. In this report, we demonstrate that V-SEA preferentially interacts with Gab2. Furthermore by using Gab2 null fibroblasts, we demonstrate that Gab2 is essential for fibroblast transformation by V-SEA. Using mutant forms of Gab2, we show that activation of the PI3K-Akt pathway via Gab2 is required for V-SEA-induced transformation. However, efficient fibroblast transformation also requires the SHP2 interaction site on Gab2.

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Acknowledgements

We thank Drs D Bar-Sagi, P Hearing, D Morrison, B Neel and L Rohrschneider for kindly providing the reagents that made this work possible. We also thank the members of our laboratory for their helpful advice and constructive criticisms. This work was supported by NIH Public Service Grant CA28146 and the Carol Baldwin Breast Cancer Award to MJH, and American Association of Cancer Research-Susan G Komen Breast Cancer Foundation Career Development Award to HG.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, 11794-5222, NY, USA

    Irene Ischenko & Michael J Hayman

  2. Department of Pathology, Stony Brook University, Stony Brook, 11794-5222, NY, USA

    Oleksi Petrenko

  3. Division of Hematology/Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, 02215, MA, USA

    Haihua Gu

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  1. Irene Ischenko
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Correspondence to Michael J Hayman.

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Ischenko, I., Petrenko, O., Gu, H. et al. Scaffolding protein Gab2 mediates fibroblast transformation by the SEA tyrosine kinase. Oncogene 22, 6311–6318 (2003). https://doi.org/10.1038/sj.onc.1206742

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