Cellular transformation by altered expression of ana adapter protein Gab1

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An in vitro transformation system of carcinogen-treated Syrian hamster embryo (SHE) cell cultures represents multistep genetic and non-genetic changes that develop during the neoplastic progression of normal cells to tumor cells in vivo. We first examined the role of the adaptor protein Gab1 in the neoplastic progression of SHE cells. During the neoplastic progression, SHE cells showed increasing expression of a novel 87-kDa form of Gab1 with diminishing expression of the original 100-kDa Gab1. Complementary DNA encoding the 87-kDa Gab1 predicts a form of Gab1 lacking the ammo-terminal 103 ammo acids (Gab1^<^Δ1-103>), which corresponds to loss of most of the pleckstrin homology (PH) domain. Moreover, transfection and expression of Gab1^<^Δ1-103>, but not Gab1, in SHE cells enhanced their epidermal growth factor (EGF) -dependent colony formation in soft agar. Thus, an altered expression of adaptor proteins may be involved in human cancers and some chronic inflammatory diseases. Synovial … More fibroblast-like (SFL) cells from patients with rheumatoid arthritis (RA) abundantly express receptors for platelet-derived growth factor (PDGF), and stimulation with PDGF enhances both the anchorage-dependent and -independent growth of RA-SFL cells. Therefore, we next examined the roles of adapter proteins in PDGF receptor signaling in tumor-like proliferation of RA-SFL cells. Gab1 was expressed in RA-SFL cells, and was rapidly tyrosine-phosphorylated after PDGF stimulation. The inhibition of PDGF receptor tyrosine kinase activation by imatinib mesylate, a key drug in the treatment of chronic myeloid leukemia, suppressed the PDGF-dependent tyrosine phosphorylation of these adapter proteins. Moreover, imatinib mesylate abolished both the anchorage-dependent and -independent proliferation of RA-SFL cells induced by PDGF stimulation. These results suggest that many adapter proteins are involved in the growth factor signaling of rheumatoid synovial cells and that the inhibition of those molecules may be effective for the treatment of a part of malignancies or chronic inflammatory diseases. Less