G Proteins provide signal transduction mechanisms to seven transmembrane receptors. Recent studies have indicated that the a-subunits as well as the bg-subunits of these proteins regulate several critical signaling pathways involved in cell proliferation, di erentiation and apoptosis. Of the 17 a-subunits that have been cloned, at least ten of them have been shown to couple mitogenic signaling in ®broblast cells. Activating mutations in Ga s , Ga i2 , and Ga 12 have been correlated with di erent types of tumors. In addition, the ability of the bg-subunits to activate mitogenic pathways in di erent cell-types has been de®ned. The present review brie¯y summarizes the diverse and novel signaling pathways regulated by the a-as well as the bg-subunits of G proteins in regulating cell proliferation.

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 G i , G q , and G 12/13 . Previous studies have shown that the overexpression of wild-type Ga 12 (Ga 12 WT) results in the oncogenic transformation of NIH3T3 cells (Ga 12 WT-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 Ga 12 WT-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 Ga 12 WT-NIH3T3 with 2 lM LPA leads to the activation of Ga 12 . Stimulation of these cells with LPA promotes JNK-activation, a critical component of Ga 12 -response and cell proliferation. We also show that LPA can substitute for serum in stimulating JNK-activity, DNA synthesis, and proliferation of Ga 12 WT-NIH3T3 cells. LPA-mediated proliferative response in NIH3T3 cells involves Ga 12 , but not the closely related Ga 13 . Pretreatment of Ga 12 WT-NIH3T3 cells with suramin (100 lM), a receptor-uncoupling agent, inhibited LPAstimulated proliferation of these cells by 55% demonstrating the signal coupling between cell surface LPAR and Ga 12 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, Ga 12 , and the downstream effectors is likely to unravel additional targets for novel cancer chemotherapies.

The isolation and characterization of multiple melatonin receptors in a wide range of tissues and cells signifies the functional diversity of melatonin. In different cellular environments, melatonin can regulate distinct second messengers or even positively or negatively regulate the same signal transduction pathway. The capacity by which melatonin receptors modulate the activities of various effector molecules is determined by the complement of signaling components present in any particular cell type. The specific interactions between many signaling molecules have been discerned in an increasing number of cellular systems and this information is being used to explain the physiological actions of melatonin. This review will attempt to summarize recent research by many groups that has revealed numerous subtleties of the melatonin-coupled signaling pathways.