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Alternate Paths from Epidermal Growth Factor Receptor to Akt in Malignant Versus Nontransformed Lung Epithelial Cells

ErbB3 Versus Gab1

Basic Research Program, SAIC-Frederick, Frederick, Maryland; and Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland

Correspondence and requests for reprints should be addressed to Gunamani Sithanandam, Basic Research Program, SAIC-Frederick, Building 538, Ft. Detrick, Frederick, MD 21702. 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, glycogen synthase kinase 3- (GSK3-), and cyclin D1 controls cell growth, survival, and invasiveness. We have investigated this pathway in paired transformed/nontransformed cell lines from murine peripheral lung epithelium, E9/E10 and A5/C10. The E9 and A5 carcinoma lines expressed ErbB3 and transforming growth factor- (TGF-) and responded to TGF- stimulation with protein complex formation including the p85 regulatory subunit of PI3K, activation of Akt, phosphorylation of GSK3-, and increased cyclin D1 protein and the cell cycle. ErbB3 and TGF- were not detected in the nontransformed E10 and C10 cell lines. Nevertheless, exposure of E10 or C10 cells to TGF- activated PI3K and Akt and increased cyclin D1 and cell growth. The effector pathway from the EGFR to PI3K in these nontransformed cells included the adaptor Grb2, the docking protein Gab1, and the phosphatase Shp2. Gab1 was highly expressed in E10 and C10 cells but not in the malignant E9 and A5 sister lines. Complexes of EGFR/Grb2/Gab1/Shp2 after TGF- stimulation were prominent only in E10 and C10 cells. Thus, alternate pathways downstream of EGFR regulate mitosis in these paired malignant versus nontransformed lung cell lines.

Key Words: EGFR • ErbB3 • Gab1 • Akt • lung epithelial cells

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