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Carcinogenesis Advance Access originally published online on January 12, 2008
Carcinogenesis 2008 29(3):647-655; doi:10.1093/carcin/bgn009
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells

Isolde Seiden-Long1,{dagger}, Roya Navab1,{dagger}, Warren Shih1, Ming Li1, Jane Chow1, Chang Qi Zhu1, Nikolina Radulovich1, Caroline Saucier4 and Ming-Sound Tsao1,2,3,*

1 Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
2 Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 1L5 and
4 Depatment of Anatomy and Cell Biology, Faculty of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4

* To whom correspondence should be addressed. Tel: +416 340 4737; Fax: +416 340 5571; Email: ming.tsao{at}uhn.on.ca

Hepatocyte growth factor receptor (Met) plays an important role in the progression of multiple cancer types. The overexpression of Met in DLD-1 colon carcinoma cells with kirsten rat sarcoma oncogene homolog (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 MetK1110A, Src homology 2 (SH2)-binding domain-inactive MetY1349/1356F, growth factor receptor-bound protein 2 (Grb2) non-binding MetN1358H and mutant receptors with ability to selectively recruit signaling proteins Grb2, src homology domain c-terminal adaptor homolog (Shc), phospholipase c-gamma (PLC{gamma}) and p85 phosphatidyl inositol 3 kinase. 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, whereas the expression of N1358H mutant stimulated tumor growth rate comparable with 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 Grb2-associated adaptor protein 1 (Gab1) protein levels, which was not observed in the cell lines, consistent with a post-translationally regulated process. Moreover, a moderate level of Gab1 overexpression stimulated tumor growth. The findings suggest a delicate balance for intact Y1349/1356 SH2-binding domain to mediate the tumor progression activity of the coactivated Met–rat sarcoma oncogene homolog (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.

Abbreviations: c-Cbl, Casitas B-lineage lymphoma proto-oncogene; Crk, Sarcoma CT10 oncogene homolog; Gab1, Grb2-associated adaptor protein 1; Gab1WT, Gab1 wild type; GFP, green fluorescent protein; HGF, hepatocyte growth factor; KRAS, Kirsten rat sarcoma oncogene homolog; mRNA, messenger RNA; MAPK, mitogen-activated protein kinase; Met, hepatocyte growth factor receptor; MetWT, wild-type Met; PCR, polymerase chain reaction; PI3K, phosphatidyl inositol 3 kinase; PLC, phospholipase c-gamma; RAS, rat sarcoma oncogene homolog; SH2, Src homology 2; Shc, Src homology domain c-terminal adaptor homolog; Shp2, Src homology-containing tyrosine phosphatase 2; ShRNA, short hairpin RNA; RT-qPCR, reverse transcriptase quantitative polymerase chain reaction; Tpr, translocated promoter region

{dagger} 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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