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

Oncogene volume 25, pages 899–906 (2006)Cite this article

Abstract

Gα12, the α-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 Gα12 involves the receptor tyrosine kinase platelet derived growth factor receptor-α (PDGFRα) and JAK3. In the present study, we demonstrate that the GTPase-deficient activated mutant of Gα12 activates signal transducer and activator of transcription 3 (STAT3) via PDGFRα as well as JAK3. Here we show that Gα12 stimulates the phosphorylation of STAT3 at both Tyrosine-705 and Serine-727 residues. Studies to delineate the mechanism by which Gα12 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, PDGFRα 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 Gα12QL-transfectants, thereby establishing the critical role of STAT3 in Gα12QL-mediated neoplastic cell growth. The results presented here demonstrate, for the first time, the ability of Gα12 to recruit multiple receptor-, nonreceptor-, and Ser/Thr kinases to stimulate STAT3-signaling to promote neoplastic transformation.

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Abbreviations

RTKs:

Receptor tyrosine kinases

GPCR:

G protein coupled receptors

G protein:

guanine nucleotide-binding protein

PDGFR:

platelet derived growth factor receptor

PI3K:

phosphatidylinositol-3-OH-kinase

JAK:

Janus kinase

STAT:

signal transducer and activator of transcription

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Acknowledgements

The critical reading of the manuscript by Ms Kimia Kashef, Mr Zachariah Goldsmith, and Dr V Radhika is gratefully appreciated. This work was supported by grants from the National Institutes of Health (GM49897).

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  1. Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    R N Kumar, S K Shore & N Dhanasekaran

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  1. R N Kumar
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Correspondence to N Dhanasekaran.

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Kumar, R., Shore, S. & Dhanasekaran, N. Neoplastic transformation by the gep oncogene, Gα12, involves signaling by STAT3. Oncogene 25, 899–906 (2006). https://doi.org/10.1038/sj.onc.1209132

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