| Gastrointestinal peptide signalling in health and disease. | |
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MedLine Citation:
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PMID: 16144198 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lung, pancreas, and colon. |
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Authors:
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Enrique Rozengurt; Sushovan Guha; James Sinnett-Smith |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: The European journal of surgery. Supplement. : = Acta chirurgica. Supplement Volume: - ISSN: 1102-416X ISO Abbreviation: Eur J Surg Suppl Publication Date: 2002 |
Date Detail:
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Created Date: 2005-09-07 Completed Date: 2005-12-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9114489 Medline TA: Eur J Surg Suppl Country: Norway |
Other Details:
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Languages: eng Pagination: 23-38 Citation Subset: IM |
Affiliation:
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Department of Medicine, School of Medicine and Molecular Biology Institute, University of California, Los Angeles 90095-1786, USA. erozengurt@mednet.ucla.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bombesin / physiology Carcinoma, Small Cell / physiopathology Cholecystokinin / physiology Colonic Neoplasms / physiopathology Gastrins / physiology Humans Lung Neoplasms / physiopathology Mice Neuropeptides / physiology* Neurotensin / physiology Pancreatic Neoplasms / physiopathology Phosphorylation Protein Kinase C / physiology Receptor, Epidermal Growth Factor / physiology Receptors, Leukotriene B4 Receptors, Purinergic P2 / physiology Signal Transduction / physiology* Swiss 3T3 Cells rho GTP-Binding Proteins / physiology |
| Chemical | |
Reg. No./Substance:
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0/Gastrins; 0/LTB4R protein, human; 0/Ltb4r1 protein, mouse; 0/Neuropeptides; 0/Receptors, Leukotriene B4; 0/Receptors, Purinergic P2; 31362-50-2/Bombesin; 39379-15-2/Neurotensin; 9011-97-6/Cholecystokinin; EC 2.7.10.-/protein kinase D; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.13/Protein Kinase C; EC 3.6.5.2/rho GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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