Neoplastic transformation by the gep oncogene, Gα12, involves signaling by STAT3

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Abstract
G12, the -subunit of G12, which has been referred to as the gep oncogene, stimulates mitogenic pathways in different cell types and readily induces neoplastic transformation of fibroblast cell lines. Recently, we have shown that the oncogenic pathway activated by G12 involves the receptor tyrosine kinase platelet derived growth factor receptor- (PDGFR) and JAK3. In the present study, we demonstrate that the GTPase-deficient activated mutant of G12 activates signal transducer and activator of transcription 3 (STAT3) via PDGFR as well as JAK3. Here we show that G12 stimulates the phosphorylation of STAT3 at both Tyrosine-705 and Serine-727 residues. Studies to delineate the mechanism by which G12 stimulates STAT3 have indicated that the Tyrosine-705-phosphorylation of STAT3 involves the tyrosine kinases, Janus Kinase-3 as well as Src kinase, whereas the Serine-727 phosphorylation of STAT3 occurs via the receptor tyrosine kinase, PDGFR and phosphatidylinositol 3-OH kinase pathway. Our results also indicate that the coexpression of the dominant negative, DNA binding mutant of STAT3 (STAT3DB) inhibits the foci formation as well as anchorage-independent growth of G12QL-transfectants, thereby establishing the critical role of STAT3 in G12QL-mediated neoplastic cell growth. The results presented here demonstrate, for the first time, the ability of G12 to recruit multiple receptor-, nonreceptor-, and Ser/Thr kinases to stimulate STAT3-signaling to promote neoplastic transformation.