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MBC in Press, published online ahead of print June 14, 2006
Mol. Biol. Cell 10.1091/mbc.E06-03-0244

A more recent version of this article appeared on September 1, 2006
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Submitted on March 28, 2006
Revised on April 18, 2006
Accepted on June 2, 2006

Gab1 Is Required for Cell-Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor

Kathleen Mood,*{dagger} Caroline Saucier,{dagger}{ddagger} Yong-Sik Bong,* Hyun-Shik Lee,* Morag Park,{ddagger}{sect} and Ira O. Daar*

*Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD 21702; {ddagger}Molecular Oncology Group and {sect}Departments of Biochemistry, Medicine, and Oncology, McGill University Health Center, Montreal, Quebec, Canada H3A 1A1

Monitoring Editor: Gerard Evan

We have shown previously that either Grb2 or Shc mediated signaling from the oncogenic Met receptor, Tpr-Met, is sufficient to trigger cell-cycle progression in Xenopus oocytes. However, direct binding of these adaptors to Tpr-Met is dispensable, implying that another Met-binding partner mediates these responses. In this study, we show that overexpression of Grb2-associated binder 1 (Gab1) promotes cell-cycle progression when Tpr-Met is expressed at suboptimal levels. This response requires that Gab1 possess an intact Met-binding motif, the pleckstrin homology domain, and the binding sites for PI3K and tyrosine phosphatase SHP-2, but not the Grb2 and CrkII/PLC{gamma} binding sites. Importantly, we establish that Gab1-mediated signals are critical for cell-cycle transition promoted by the oncogenic Met and FGF receptors, but not by progesterone, the natural inducer of cell-cycle transition in Xenopus oocytes. Moreover, Gab1 is essential for Tpr-Met-mediated morphological transformation and proliferation of fibroblasts. This study provides the first evidence that Gab1 is a key binding partner of the Met receptor for induction of cell-cycle progression, proliferation, and oncogenic morphological transformation. This identifies Gab1 and its associated signaling partners as potential therapeutic targets to impair proliferation or transformation of cancer cells in human malignancies harboring a deregulated Met receptor.

{dagger}These authors contributed equally to this work.

Address correspondence to: Ira O. Daar (daar{at}ncifcrf.gov)




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