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


RESULTS
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.


CONCLUSIONS
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.
Oyesanya
Regina A
RA
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Greenbaum
Susie
S
Dang
David
D
Lee
Zendra
Z
Mukherjee
Abir
A
Wu
Jinhua
J
Dent
Paul
P
Fang
Xianjun
X
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019000:Phosphotyrosine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; C032881:lysophosphatidic acid