Neoplastic transformation by the gep oncogene, Galpha12, involves signaling by STAT3.
Galpha(12), the alpha-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 Galpha(12) involves the receptor tyrosine kinase platelet derived growth factor receptor-alpha (PDGFRalpha) and JAK3. In the present study, we demonstrate that the GTPase-deficient activated mutant of Galpha(12) activates signal transducer and activator of transcription 3 (STAT3) via PDGFRalpha as well as JAK3. Here we show that Galpha(12) stimulates the phosphorylation of STAT3 at both Tyrosine-705 and Serine-727 residues. Studies to delineate the mechanism by which Galpha(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, PDGFRalpha 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 Galpha(12)QL-transfectants, thereby establishing the critical role of STAT3 in Galpha(12)QL-mediated neoplastic cell growth. The results presented here demonstrate, for the first time, the ability of Galpha(12) to recruit multiple receptor-, nonreceptor-, and Ser/Thr kinases to stimulate STAT3-signaling to promote neoplastic transformation.
Kumar
R N
RN
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, PA 19140, USA.
Shore
S K
SK
Dhanasekaran
N
N
D016475:3T3 Cells / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053616:Janus Kinase 3; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D050796:STAT3 Transcription Factor; D014443:Tyrosine; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D019061:src-Family Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13