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

Abstract

Ga 12 , the a-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 Ga 12 involves the receptor tyrosine kinase platelet derived growth factor receptor-a (PDGFRa) and JAK3. In the present study, we demonstrate that the GTPase-deficient activated mutant of Ga 12 activates signal transducer and activator of transcription 3 (STAT3) via PDGFRa as well as JAK3. Here we show that Ga 12 stimulates the phosphorylation of STAT3 at both Tyrosine-705 and Serine-727 residues. Studies to delineate the mechanism by which Ga 12 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, PDGFRa 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 Ga 12 QL-transfectants, thereby establishing the critical role of STAT3 in Ga 12 QL-mediated neoplastic cell growth. The results presented here demonstrate, for the first time, the ability of Ga 12 to recruit multiple receptor-, nonreceptor-, and Ser/Thr kinases to stimulate STAT3-signaling to promote neoplastic transformation.

Activation of STAT3 by Gαs Distinctively Requires Protein Kinase A, JNK, and Phosphatidylinositol 3-Kinase

“…Among the many transcription factors identified to date, the STAT proteins are the most well established in terms of their regulation by G proteins. Members of the G i/o , G q , and G 12 families have been reported to stimulate STAT3 Tyr 705 and Ser 727 phosphorylations through several common signaling intermediates such as Src and MAPKs (26, 27,46,47). Despite the fact that a number of G s -coupled receptors have been reported to activate STAT3 (28,29,48), very little is known with regard to their mechanism of action.…”

Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes

“…Constitutive G␣ 12 signaling can mediate oncogenic transformation through Src-and PI3k-Akt-mediated activation of STAT3. 38 We and others have shown that Src-family kinases, PI3K-AKT, and STAT3 activation contribute to apoptotic resistance of leukemic LGLs. 9,12 Taken together, these facts suggest that altered sphingolipid-mediated signaling through S1P 5 -G␣ 12 may play an important role in survival of leukemic LGLs.…”

Gα12-Mediated Pathway Promotes Invasiveness of Nasopharyngeal Carcinoma by Modulating Actin Cytoskeleton Reorganization

“…Ga 12 has been found to activate oncogenic transformation and tumor cell invasion (18)(19)(20), although it is not known whether it is also involved in epithelial-to-mesenchymal transition (EMT). EMT is a pathophysiologic process of tumor cells characterized by loss of epithelial junctional proteins and cell polarity and gain of mesenchymal markers.…”