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Published ahead of print on July 29, 2005, doi:10.1165/rcmb.2005-0049OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 5, November 2005, 490-499

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Submitted on February 1, 2005
Revised on July 26, 2005

Alternate Paths from EGFR to Akt in Malignant vs Non-transformed Lung Epithelial Cells:ErbB3 vs Gab1

Gunamani Sithanandam1*, George T Smith2, Janet R Fields2, Laura W Fornwald1, and Lucy M Anderson2

1 Basic Research Program, SAIC Frederick, Frederick, MD, USA, 2 Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD, USA

* To whom correspondence should be addressed. E-mail: sithanan{at}ncifcrf.gov.

In many human lung adenocarcinoma cell lines, a pathway involving epidermal growth factor receptor (EGFR), ErbB2 and ErbB3 receptors, phosphatidyl inositol 3-kinase (PI3K), Akt, GSK3{beta}, and cyclin D1 controls cell growth, survival, and invasiveness. We have investigated this pathway in paired transformed/non-transformed cell lines from murine peripheral lung epithelium, E9/E10 and A5/C10. The E9 and A5 carcinoma lines expressed ErbB3 and transforming growth factor alpha (TGF{alpha}), and responded to TGF{alpha} stimulation with protein complex formation including the p85 regulatory subunit of PI3K, activation of Akt, phosphorylation of GSK3{beta}, and increased cyclin D1 protein and the cell cycle. On the contrary, ErbB3 and TGF{alpha} were not detected in the non-transformed E10 and C10 cell lines. Nevertheless, exposure of E10 or C10 cells to TGF{alpha} activated PI3K and Akt, and increased cyclin D1 and cell growth. The effector pathway from the EGFR to PI3K in these non-transformed cells included the adaptor Grb2, the docking protein Gab1, and the phosphatase Shp2. Gab1 was highly expressed in E10 and C10 cells, not in the malignant E9 and A5 sister lines. Complexes of EGFR/Grb2/Gab1/Shp2 after TGF{alpha} stimulation were prominent only in E10 and C10 cells. Thus alternate pathways downstream of EGFR regulate mitosis in these paired malignant vs non-transformed lung cell lines.




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