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Molecular and Cellular Biology, October 2001, p. 6895-6905, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6895-6905.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Expression of Gab1 Lacking the Pleckstrin Homology Domain Is Associated with Neoplastic Progression

Hideto Kameda,1,2 John I. Risinger,1 Bing-Bing Han,1 Seung Joon Baek,1 J. Carl Barrett,1 Tohru Abe,2 Tsutomu Takeuchi,2 Wayne C. Glasgow,3 and Thomas E. Eling1,*

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 277091; Department of Internal Medicine, Saitama Medical Center, Kawagoe, Saitama 350, Japan2; and Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia 312073

Received 28 September 2000/Returned for modification 1 December 2000/Accepted 19 July 2001

An in vitro transformation system of carcinogen-treated Syrian hamster embryo (SHE) cell cultures represents multistep genetic and nongenetic changes that develop during the neoplastic progression of normal cells to tumor cells in vivo. During this neoplastic progression, SHE cells demonstrate an altered response to epidermal growth factor (EGF). In the present report, we examined the role of the adapter protein Gab1 (Grb2-associated binder-1) in the neoplastic progression of SHE cells. We used two asbestos-transformed SHE cell clones in different neoplastic stages: a 10W+8 clone, which is immortal and retains the ability to suppress the tumorigenicity of tumor cells in cell-cell hybrid experiments, and a 10W-1 clone, which has lost this tumor suppressor ability. 10W+8 cells expressed full-length 100-kDa Gab1 and associated 5.2-kb mRNA. Upon repeated cell passaging, 10W-1 cells showed increasing expression of a novel 87-kDa form of Gab1 as well as 4.6-kb mRNA with diminishing expression of the original 100-kDa Gab1. cDNA encoding the 87-kDa Gab1 predicts a form of Gab1 lacking the amino-terminal 103 amino acids (Gab1Delta 1-103), which corresponds to loss of most of the pleckstrin homology (PH) domain. Gab1Delta 1-103 retains the ability to be phosphorylated in an EGF-dependent manner and to associate with the EGF receptor and SHP-2 upon EGF stimulation. The endogenous expression of Gab1Delta 1-103 in 10W-1 cells appeared closely related to EGF-dependent colony formation in soft agar. Moreover, transfection and expression of Gab1Delta 1-103, but not Gab1, in 10W+8 cells enhanced their EGF-dependent colony formation in soft agar. These results demonstrate that Gab1 is a target of carcinogen-induced transformation of SHE cells and that the expression of a Gab1 variant lacking most of the PH domain plays a specific role in the neoplastic progression of SHE cells.

* Corresponding author. Mailing address: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences/NIH, P.O. Box 12233, Research Triangle Park, NC 27709. Phone: (919) 541-3911. Fax: (919) 541-0146. E-mail: Eling{at}niehs.nih.gov.

Molecular and Cellular Biology, October 2001, p. 6895-6905, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6895-6905.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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