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Gab1 is required for EGF receptor signaling and the transformation by activated ErbB2

Oncogene volume 22, pages 1546–1556 (2003)Cite this article

Abstract

Grb2-associated binder-1 (Gab1) is a pleckstrin homology (PH) domain-containing adapter molecule that is believed to function downstream of receptors for growth factors and cytokines. We previously found that deficiency in the mouse Gab1 gene led to embryonic lethality and defects in ERK activation in response to growth factors and cytokines. Here, we established immortalized Gab1−/− cell lines and analysed roles of Gab1 in growth factor-mediated signaling and oncogenesis. EGF-dependent activation of c-Raf and Mek1/2, which function upstream of ERKs, was perturbed in Gab1−/− cells. EGF-mediated upregulation of GTP-bound form of Ras was also reduced in these cells. EGF-dependent GTP/GDP exchange activity for Ras was suppressed in the Gab1−/− cells and expression of a constitutively active Sos restored ERK activation in these cells, indicating that Gab1 functions upstream of Ras. Furthermore, activated form of ErbB2 (active ErbB2)-mediated transformation, such as colony formation in soft agar and tumor formation in nude mice, was strongly suppressed when the Gab1−/− cells were transfected with active ErbB2, whereas the active Sos efficiently induced transformation of Gab1−/− cells. The data show that Gab1 plays an essential role in EGF-receptor/ErbB-mediated cell proliferation and oncogenesis.

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Acknowledgements

We thank Drs T Yamamoto, K Yoshioka, A Aronhemi, S Hattori, and H Niwa for various reagents. We thank Ms R Masuda and A Kubota for secretarial assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and the Osaka Foundation for the Promotion of Clinical Immunology.

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Author notes

  1. Motoyuki Itoh

    Present address: Unit of Vertebrate Neural Development, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development/National Institutes of Health, Building 6B, Room 3B-315, 9000 Rockville Pike, Bethesda, MD, 20892, USA

  2. Masahiko Hibi

    Present address: Laboratory for Vertebrate Axis Formation, Center for Developmental Biology, RIKEN, Kobe, Japan

Authors and Affiliations

  1. Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, Osaka, Japan

    Satoru Yamasaki, Yuichi Yoshida, Motoyuki Itoh, Masahiko Hibi & Toshio Hirano

  2. Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan

    Toshio Hirano

  3. Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Kanagawa, Japan

    Keigo Nishida & Toshio Hirano

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  1. Satoru Yamasaki
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Correspondence to Toshio Hirano.

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Yamasaki, S., Nishida, K., Yoshida, Y. et al. Gab1 is required for EGF receptor signaling and the transformation by activated ErbB2. Oncogene 22, 1546–1556 (2003). https://doi.org/10.1038/sj.onc.1206284

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