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Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

Oncogene volume 24, pages 4597–4603 (2005)Cite this article

Abstract

Lysophosphatidic acid (LPA), a major G protein coupled receptor (GPCR)-activating ligand present in serum, elicits growth factor like responses by stimulating specific GPCRs coupled to heterotrimeric G proteins such as Gi, Gq, and G12/13. Previous studies have shown that the overexpression of wild-type Gα12 (Gα12WT) results in the oncogenic transformation of NIH3T3 cells (Gα12WT-NIH3T3) in a serum-dependent manner. Based on the potent growth-stimulating activity of LPA and the presence of LPA and LPA-like molecules in the serum, we hypothesized that the serum-dependent neoplastic transformation of Gα12WT-NIH3T3 cells was mediated by the stimulation of LPA-receptors (LPARs) by LPA in the serum. In the present study, using guanine nucleotide exchange assay and GST-TPR binding assay, we show that the treatment of Gα12WT-NIH3T3 with 2 μ M LPA leads to the activation of Gα12. Stimulation of these cells with LPA promotes JNK-activation, a critical component of Gα12-response and cell proliferation. We also show that LPA can substitute for serum in stimulating JNK-activity, DNA synthesis, and proliferation of Gα12WT-NIH3T3 cells. LPA-mediated proliferative response in NIH3T3 cells involves Gα12, but not the closely related Gα13. Pretreatment of Gα12WT-NIH3T3 cells with suramin (100 μ M), a receptor-uncoupling agent, inhibited LPA-stimulated proliferation of these cells by 55% demonstrating the signal coupling between cell surface LPAR and Gα12 in the neoplastic proliferation of NIH3T3 cells. As LPA and LPAR mediated mitogenic pathways have been shown to play a major role in tumor genesis and progression, a mechanistic understanding of the signal coupling between LPAR, Gα12, and the downstream effectors is likely to unravel additional targets for novel cancer chemotherapies.

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Abbreviations

LPA:

lysophosphatidic acid

G protein:

guanine nucleotide binding protein

GPCR:

G protein coupled receptor

JNK:

Jun N-terminal kinase

LPAR:

lysophosphatidic acid receptor

PTX:

pertussis toxin.

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Acknowledgements

We thank Professor M Negishi, Kyoto University, Japan, for the generous gift of GST-TPR encoding pGEX-4T-2-GST-TPR construct. Helpful discussions and critical reading of the manuscript by Mr Zachariah G Goldsmith, Ms Rashmi Kumar, and Ms Kimia Kashef are gratefully acknowledged. 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 Medicine, Philadelphia, PA, 19140, USA

    V Radhika, Ji Hee Ha, Muralidharan Jayaraman, Siu-Tai Tsim & N Dhanasekaran

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Correspondence to N Dhanasekaran.

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Radhika, V., Hee Ha, J., Jayaraman, M. et al. Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12. Oncogene 24, 4597–4603 (2005). https://doi.org/10.1038/sj.onc.1208665

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