Differential requirement of the epidermal growth factor receptor for G protein-mediated activation of transcription factors by lysophosphatidic acid

• Main Authors: Dent Paul, Wu Jinhua, Mukherjee Abir, Lee Zendra, Dang David, Greenbaum Susie, Oyesanya Regina A, Fang Xianjun
• Format: Article
• Language: English
• Published: BMC 2010-01-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/9/1/8

<p>Abstract</p> <p>Background</p> <p>The role of the epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in provoking biological actions of G protein-coupled receptors (GPCRs) has been one of the most disputed subjects in the field of GPCR signal transduction. The purpose of the current study is to identify EGFR-mediated mechanisms involved in activation of G protein cascades and the downstream transcription factors by lysophosphatidic acid (LPA).</p> <p>Results</p> <p>In ovarian cancer cells highly responsive to LPA, activation of AP-1 by LPA was suppressed by inhibition of EGFR, an effect that could be reversed by co-stimulation of another receptor tyrosine kinase c-Met with hepatocyte growth factor, indicating that LPA-mediated activation of AP-1 requires activity of a RTK, not necessarily EGFR. Induction of AP-1 components by LPA lied downstream of Gi, G12/13, and Gq. Activation of the effectors of Gi, but not Gq or G12/13 was sensitive to inhibition of EGFR. In contrast, LPA stimulated another prominent transcription factor NF-κB via the Gq-PKC pathway in an EGFR-independent manner. Consistent with the importance of Gi-elicited signals in a plethora of biological processes, LPA-induced cytokine production, cell proliferation, migration and invasion require intact EGFR.</p> <p>Conclusions</p> <p>An RTK activity is required for activation of the AP-1 transcription factor and other Gi-dependent cellular responses to LPA. In contrast, activation of G12/13, Gq and Gq-elicited NF-κB by LPA is independent of such an input. These results provide a novel insight into the role of RTK in GPCR signal transduction and biological functions.</p>