G protein-coupled receptor (GPCR) agonists, including neurotransmitters, hormones, chemokines, and bioactive lipids, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. Typically, the binding of an agonistic ligand to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the activity of phospholipases C, D, and A2 leading to the synthesis of lipid-derived second messengers, Ca 2þ fluxes and subsequent activation of protein phosphorylation cascades, including PKC/PKD, Raf/MEK/ERK, and Akt/ mTOR/p70S6K is an important early response to mitogenic GPCR agonists. The EGF receptor (EGFR) tyrosine kinase has emerged as a transducer in the signaling by GPCRs, a process termed transactivation. GPCR signal transduction also induces striking morphological changes and rapid tyrosine phosphorylation of multiple cellular proteins, including the non-receptor tyrosine kinases Src, focal adhesion kinase (FAK), and the adaptor proteins CAS and paxillin. The pathways stimulated by GPCRs are extensively interconnected by synergistic and antagonistic crosstalks that play a critical role in signal transmission, integration, and dissemination. The purpose of this article is to review recent advances in defining the pathways that play a role in transducing mitogenic responses induced by GPCR agonists.
A rapid increase in the synthesis of lipid-derived second messengers is an important mechanism for transducing extracellular signals across the plasma membrane (1-3). The phospholipase C-mediated hydrolysis of inositol phospholipids is known to produce two second messengers: inositol 1,4,5-trisphosphate, which induces mobilization of calcium from intracellular stores (3), and diacylglycerol (DAG), which activates protein kinase C (PKC)-originally described as a Ca2+-activated, phospholipid-dependent protein kinase (4). The early findings that the potent tumor promoters of the phorbol ester family can substitute for DAG in PKC activation and that the phorbol ester receptor and PKC copurify supported the hypothesis that the cellular target of the phorbol esters is PKC (4). Subsequent studies revealed the diversity of the individual components of the DAG-PKC signal transduction pathway.
Although a role for the gastric and intestinal mucosa in molecular sensing has been known for decades, the initial molecular recognition events that sense the chemical composition of the luminal contents has remained elusive. Here we identified putative taste receptor gene transcripts in the gastrointestinal tract. Our results, using reverse transcriptase-PCR, demonstrate the presence of transcripts corresponding to multiple members of the T2R family of bitter taste receptors in the antral and fundic gastric mucosa as well as in the lining of the duodenum. In addition, cDNA clones of T2R receptors were detected in a rat gastric endocrine cell cDNA library, suggesting that these receptors are expressed, at least partly, in enteroendocrine cells. Accordingly, expression of multiple T2R receptors also was found in STC-1 cells, an enteroendocrine cell line. The expression of ␣ subunits of G proteins implicated in intracellular taste signal transduction, namely G␣gust, and G␣t-2, also was demonstrated in the gastrointestinal mucosa as well as in STC-1 cells, as revealed by reverse transcriptase-PCR and DNA sequencing, immunohistochemistry, and Western blotting. Furthermore, addition of compounds widely used in bitter taste signaling (e.g., denatonium, phenylthiocarbamide, 6-n-propil-2-thiouracil, and cycloheximide) to STC-1 cells promoted a rapid increase in intracellular Ca 2؉ concentration. These results demonstrate the expression of bitter taste receptors of the T2R family in the mouse and rat gastrointestinal tract.stomach ͉ intestine ͉ gustducin ͉ transducin T he gustatory system has been selected during evolution to detect nutritive and beneficial compounds as well as harmful or toxic substances (1, 2). In particular, bitter taste has evolved as a central warning signal against the ingestion of potentially toxic substances (3). Recently, a large family of bitter taste receptors (T2Rs) expressed in specialized neuroepithelial taste receptor cells organized within taste buds in the tongue has been identified in humans and rodents (4-6). These putative taste receptors, which belong to the guanine nucleotide-binding regulatory protein (G protein)-coupled receptor superfamily characterized by seven putative transmembrane domains, are distantly related to V1R vomeronasal receptors and opsins (5). Genetic and biochemical evidence indicate that specific G␣ subunits, gustducin (G␣ gust ) and transducin (G␣ t ), mediate bitter and sweet gustatory signals in the taste buds of the lingual epithelium (7-11).Outside the tongue, expression of G␣ gust also has been localized to gastric (12) and pancreatic (13) cells, suggesting that a taste-sensing mechanism also may exist in the gastrointestinal (GI) tract. However, not all cells that express G␣ gust also coexpress members of the T2R family of receptors (5). For example, most G␣ gust -positive taste receptor cells in the lingual fungiform papillae are T2R-negative, implying that G␣ gust also could mediate signaling through other receptors (9). To establish that the gastric an...
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