CCKBR-Gastrin Stimulated Signaling
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CCKBR-Gastrin Stimulated Signaling
Multicellular organisms have developed highly efficient mechanisms of cell communication to integrate and coordinate the function and proliferation of individual cell types. Gastrointestinal peptides, including Gastrin and CCK (Cholecystokinin), are a structurally diverse group of molecular messengers that function in a rich network of information exchange systems throughout the organism. Gastrin, produced by G-Cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of ECL (Enterochromaffin-like Cells), and neoplastic transformation. The binding of Gastrin or CCK to their common cognate recseptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation (Ref.1).

Gastrin, CCK, and CCK-related peptides exert their effects by binding to specific GPCR (G Protein-Coupled Receptors) subtypes. The CCKBR (also known as CCK2)/Gastrin receptor binds Gastrin and CCK with similar affinity, whereas the CCKAR (also called CCK1) exhibits a 500-fold higher affinity for CCK than for Gastrin. One of the earliest events to occur after the binding of many gastrointestinal peptides agonists to their GPCRs is the activation of G-Proteins of the G-AlphaQ subfamily and the exchange of GDP bound to the G-AlphaQ for GTP. The resulting GTP-G-AlphaQ complex, in turn, activates PLC-Beta (Phospholipase-C-Beta), which catalyze the hydrolysis of PIP2 (Phosphatidyl Inositol 4, 5-Bisphosphate) in the plasma membrane to produce two second messengers: IP3 (Inositol 1, 4, 5-Trisphosphate) and DAG (Diacylglycerol). IP3 binds to its intracellular receptor, a ligand-gated Ca2+ channel located in the Endoplasmic Reticulum, and triggers the release of Ca2+ from internal stores (Ref.2 & 3). DAG directly activates the isoforms of PKC (Protein Kinase-C) which stimulates PYK2 (Proline-rich Tyrosine Kinase-2). In epithelial cells a likely chain of events is Gastrin-induced (PLC-dependent) PKC activation and Ca2+ mobilization, PYK2-mediated stimulation of c-Src activation, and MAPK (Mitogen Activated Protein Kinase) activation via tyrosine phosphorylation of adaptor proteins including SHC , the adaptor protein GRB2 (Growth Factor Receptor-Bound Protein-2) and the guanine nucleotide release factor SOS (Son of Sevenless), which binds to tyrosine kinase receptors and promotes the accumulation of p21Ras-GTP. MAPK signal transduction pathways constitute one of the major mechanisms by which extracellular stimuli by these agonists are converted into specific nuclear responses. Four families of MAPK including ERK1/2 (Extracellular signal-Regulated Kinase), JNK (c-Jun NH2-terminal Kinase), p38MAPK , and ERK5 are involved and these kinases are regulated by their upstream specific MAPK, i.e. MEK1, MKK4/7, MKK3/6, and MEK5, respectively. Following MAPK activation, several other transcription factors are up-regulated, including Elk1, ATF2 (Activating Transcription Factor-2), c-Fos, c-Jun, MEF (MADS Box Transcription Enhancer Factor-2) and Activating Protein-1 Ref.4). Another potential pathway is the transactivation of the EGFR (Epidermal Growth Factor Receptor) by GPCR agonists, which also leads to p21Ras-dependent MAPK activation in a variety of cell types. Gastrin promotes the synthesis and processing of HBEGF (Heparin-Binding EGF-like Growth Factor) and induces tyrosine phosphorylation of EGFR (Ref.5).

In addition to eliciting the synthesis of classic second messengers and the consequent stimulation of multiple serine/threonine protein kinase cascades, these agonists also induce tyrosine phosphorylation of multiple proteins. The G-Alpha12 and G-Alpha13, which make up the G12 subfamily of heterotrimeric G-Proteins, stimulate Rho-dependent actin stress fiber formation, focal adhesion assembly, and tyrosine phosphorylation of focal adhesion proteins. The activated forms of G-Alpha12/G-Alpha13 activate Rho exchange factors that promote the GTP-bound form of Rho, and thereby lead to tyrosine phosphorylation of p125FAK (Focal Adhesion Kinase), PYK2, and Src (Ref.3). Complex formation between p125FAKand Src results in the tyrosine phosphorylation of p125FAK at additional sites that stimulate its activity and provide docking sites for other signaling proteins. The focal adhesion proteins Paxillin and p130CAS (Crk-Associated Substrates) are potential downstream targets for p125FAK and function as adaptors in signal transduction. The Ser/Thr protein kinase ROCK (Rho-associated coiled-coil-forming Protein Kinase) acts as a downstream target of Rho-GTP that transduces Rho activation into cytoskeletal responses, although other targets of Rho also contribute to this process. ROCK activation leads to a Ca2+-independent increase in the phosphorylation of MLC (Myosin Light Chain) at serine 19 and Myosin filament formation that stimulates interaction with Actin. The tension generated by the Actin-Myosin contractile apparatus promote the formation of stress fibers and the clustering of integrins to which they are attached, thus giving rise to focal adhesions.

Biologically active amidated gastrins act as potent cellular growth factors that are implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of pancreatic, gastric, colonic, and small cell lung tumors, and neoplastic transformation. The expression of CCKBR/Gastrin receptor in human cancers leads to autocrine/paracrine loops and endocrine stimulation that promote tumor cell proliferation and migration. A well-defined case is SCLC (Small Cell Lung Carcinoma), which accounts for 25% of pulmonary cancers and follows a very aggressive clinical course (Ref.5).