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

• Published in: Molecular cancer Vol. 9; no. 1; p. 8
• Main Authors: Oyesanya, Regina A, Greenbaum, Susie, Dang, David, Lee, Zendra, Mukherjee, Abir, Wu, Jinhua, Dent, Paul, Fang, Xianjun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.01.2010; BioMed Central; BMC
• Subjects: Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cellular signal transduction; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Female; G proteins; Genetic aspects; GTP-Binding Proteins - metabolism; Hepatocyte Growth Factor - pharmacology; Humans; Interleukin-8 - biosynthesis; Lysophospholipids - pharmacology; Neoplasm Invasiveness; NF-kappa B - metabolism; Phosphotyrosine - metabolism; Physiological aspects; Transcription Factor AP-1 - metabolism; Transcription factors; United States
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-8

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). 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-kappaB 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. 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-kappaB 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.