Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn009
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Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells
1 Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada M5G 2M9
2 Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
3 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
4 Molecular Oncology Group, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1
Address all correspondence to: Dr. Ming-Sound Tsao, Room 7-613, Princes Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: 416-340-4737; Fax: 416-340-5571; Email: Ming.Tsao{at}uhn.on.ca
Hepatocyte growth factor (HGF) receptor Met plays an important role in the progression of multiple cancer types. The overexpression of Met in DLD-1 colon carcinoma cells with KRAS oncogene activation resulted in enhanced subcutaneous and orthotopic tumor growth rate and increased metastatic potential. To elucidate the mechanism of this effect, we stably expressed kinase inactive Met K1110A, SH2 binding domain inactive Met Y1349/1356F, Grb2 non-binding Met N1358H, and mutant receptors with ability to selectively recruit signaling proteins Grb2, Shc, PLC
and p85 PI3K. As subcutaneous implants, DLD-1 cells that expressed the majority of these receptor constructs failed to recapitulate the tumor growth enhancing effect of the wild type Met receptor. The Grb2 and Shc-recruiting Met mutants demonstrated slight but consistent tumor suppressive activity, while the expression of N1358H mutant stimulated tumor growth rate comparable to the wild type receptor. This suggests that direct Grb2/Shc binding does not contribute to the tumor progression activity of Met receptor. The tumors expressing Grb2 and Shc recruiting Met receptors demonstrated a marked loss in Gab1 protein levels, which was not observed in the cell lines, consistent with a post-translationally regulated process. Moreover, a moderate level of Gab1 over-expression stimulated tumor growth. The findings suggest a delicate balance for intact Y1349/1356 SH2 binding domain to mediate the tumor progression activity of the co-activated Met-RAS pathways. Selectivity for specific adaptor protein involvement may be the key that determines the tissue and cell type specificity of Met-mediated tumorigenicity in human cancers.
* Drs. Seiden-Long and Navab contributed equally to this work
Received June 29, 2007; revised November 15, 2007; accepted December 20, 2007.
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