Background Lysophosphatidic acid is a naturally occurring intercellular mediator of diverse biological functions. It is produced by acti vated platelets during coagulation and thus is a normal constituent of serum. At least six G protein Rapamycin coupled receptors of LPA have been identified. The LPA1 Edg2, LPA2 Edg4 and LPA3 Edg7 recep tors are members of the endothelial differentiation gene family and share 50 57% homology in their amino acid sequences. Recently, LPA4 p2y9 GPR23, LPA5 GPR92 and LPA6 p2y5 of the purinergic receptor family, structurally distant from the Edg LPA receptors were described as additional LPA receptors. The LPA receptors couple to multiple G proteins, G12 13, Gi, Gq, and probably Gs.

These G proteins link to diverse signaling pathways including stimulation of phospholipase C and D, inhibition of adenylyl cyclase, and activation of Inhibitors,Modulators,Libraries Ras and the downstream mitogen acti vated protein kinases and phosphoinositide 3 kinase. Activation of these signaling cascades down stream of LPA receptors culminates in morphological changes and promotion of cell growth, survival and motility. Recently, we and others demonstrated that LPA induces activation of various transcription factors, upregulating expression of many target genes involved in cell proliferation, survival, and migration and invasion. The connection of LPA and its receptors to gene expression has become an interesting focus of research to understand the molecular mechanisms of LPA signal transduction. Many biological effects of GPCR have been thought to occur through transactivation of EGFR.

In our previous studies, however, the effects of LPA on gene expression Inhibitors,Modulators,Libraries were much more potent than those of EGF or other agonists of receptor tyrosine kinases. LPA indeed induced low levels of tyrosine phos phorylation of EGFR which were in no means compar able to that stimulated by EGF itself. Intriguingly, the effect of LPA on its target gene Cox 2 was sensitive to inhibition of EGF, suggesting require ment of a permissive Inhibitors,Modulators,Libraries or parallel input from EGFR in the delivery of signals of LPA or other GPCR agonists. In the current study, we explored the role of RTK in LPA activation of G protein signaling cascades and the downstream transcription factors. Molecular and pharmacological studies indicated that activation of the effectors of Gi, but not those Inhibitors,Modulators,Libraries of Gq or G12 13 relied on EGFR.

Furthermore, activation of AP 1 components by LPA involved Gi signaling and was highly sensitive Inhibitors,Modulators,Libraries to inhibition of EGFR. We further demonstrated that this mode of crosstalk between GPCR and www.selleckchem.com/products/BAY-73-4506.html EGFR was mediated by the activity of a RTK, not necessarily EGFR. In contrast to AP 1, LPA stimulated another pro minent transcription factor NF B via the Gq PKC cas cade in an EGFR independent manner. These results demonstrate the involvement of EGFR or an alternate RTK in activation of selective G protein signaling cas cades and the downstream responses.