The G‐protein‐coupled CCK2 receptor associates with phospholipase Cγ1

Arnould, Marika; Tassa, Amina; Ferrand, Audrey; Archer, Elodie; Estève, Jean-Pierre; Pénalba, Virginie; Portolan, Ghislaine; Escherich, Achim; Moröder, Luis; Fourmy, Daniel; Seva, Catherine; Dufresne, Marlène

doi:10.1016/j.febslet.2004.05.012

Cited by 13 publications

(6 citation statements)

References 23 publications

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“…While CCKAR and CCKBR primarily activate PLCβ, PLCγ is also implicated in CCKBR-mediated signaling pathways. 52, 53 Activation of PKCs leads to subsequent activation of MAPK and other signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Role of AMP-18 in oral mucositis

et al. 2011

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Oral mucositis (OM) is a devasting toxicity associated with cytotoxic cancer therapy. Antrum mucosal protein (AMP)-18 and a synthetic peptide surrogate, exhibit cell protective and mitogenic properties in in vitro and in vivo models of gastrointestinal epithelial cell injury. The mucosal barrier-protective effects may be mediated by AMP-18 's capacity to increase accumulation of specific tight junction (TJ) and adherens junction proteins, and also protect against their loss after injury. Here we asked if AMP peptide could protect the oral mucosa and speed healing from radiation-induced injury. We found AMP peptide prevented radiation-induced OM in a murine model. The peptide also stimulated HaCaT cell growth used to model the oral mucosa. Binding of recombinant human (rh) AMP-18 to the plasma membrane of keratinocytes in normal human oral mucosal tissue suggested that its effects may be receptor mediated. Using an immobilized His-tagged rhAMP-18 fusion protein the receptor was identified as the cholecystokinin-B/gastrin receptor (CCKBR) by affinity purification and mass spectrometry analysis. CCKBR was expressed and co-immunoprecipitated with exogenous rhAMP-18 in diverse epithelial cell lines. Immunofluorescence staining revealed that rhAMP-18 colocalized with CCKBR on the surface of CCKBR-transfected cells. Furthermore, rhAMP-18-stimulated signaling pathways were blocked by a CCKBR-specific antagonist, YM022. RhAMP-18 enhanced viability and growth of CCKBR-transfected, but not empty vector-transfected cells. These results suggest the importance of epithelial junctional integrity in the pathogenesis of OM and demonstrate that AMP-18, by targeting TJ proteins through the activation of CCKBR, could provide a novel strategy for the prevention and treatment of OM.

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Section: Discussionmentioning

confidence: 99%

Role of AMP-18 in oral mucositis

et al. 2011

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“…45 Additionally, we recently reported overexpression and activation of the PLC␥1 in response to gastrin in ElasCCK2 acini, giving further support to a modification of signal transduction in these cells. 46 Interestingly, besides its known role as an early effector in signal transduction phospholipase C␥1 signaling is also postulated to be linked to cytoskeletal alterations, cellular morphological changes, and migration and therefore may contribute to the observed changes in cellular adhesion and differentiation; 47-49 4) finally, our recent demonstration of an association of phospholipase C␥1 with the C-terminal sequence of the CCK2-receptor raises the possibility of proteins complexes interacting with the CCK2 receptor, including scaffolding molecules and proteins of the cytoskeleton, for modification of cell adhesion. 46,50 Second, in the exocrine pancreas of ElasCCK2 mice we find cellular and nuclear dysplasia accompanied by reduced expression of acinar-specific markers (amylase), ultrastructural defects in the secretion pathway, and the up-regulation of ductal markers (K19).…”

Section: Discussionmentioning

confidence: 99%

Expression of Cholecystokinin-2/Gastrin Receptor in the Murine Pancreas Modulates Cell Adhesion and Cell Differentiation in Vivo

Bierkamp

Bonhoure

Mathieu

et al. 2004

The American Journal of Pathology

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The presence of gastrin and cholecystokinin-2 (CCK2) receptors in human preneoplastic and neoplastic gastrointestinal lesions suggests a role in cancer development. In addition to the growth-promoting action of gastrin, recently a role of the cholecystokinin-2/gastrin receptor (CCK2-R) modulating cellular morphology in cultured epithelial cells has been shown. Here, we have investigated in transgenic (ElasCCK2) mice whether ectopic expression of human CCK2-R in the exocrine pancreas affected epithelial differentiation. Cellular localization of cell adhesion molecules, differentiation markers, and transcription factors was determined using immunofluorescence techniques. Before tumor formation, expression and subcellular localization of proteins of the adherens junction complex, differentiation markers, and transcription factors were altered in ElasCCK2 exocrine pancreas, indicating an evolution from an acinar to a ductal phenotype. Loss of cell polarity, defective secretion, and loss of intercellular adhesion in acini of ElasCCK2 mice was confirmed by ultrastructural analysis. Finally, expression of the transgene in mice treated with the carcinogen azaserine resulted in enhanced size of preneoplastic lesions as well as an increased degree of acinar-ductal transdifferentiation. Thus, these data represent the first evidence for the CCK2-R modulating intercellular adhesion and cell fate in vivo and show that these alterations may contribute to enhanced sensitivity of ElasCCK2 pancreas to chemical carcinogens.

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“…We previously documented interaction of the C-terminal region of the CCK2R with RGS-2, SHP-2 phosphatase, or phospholipase-C ␥1 (17,47,48). The motif involved in functional binding of SHP2 phosphatase and phospholipase-C ␥1 to the CCK2R is an ITIM motif containing Tyr 438 , which, once phosphorylated, recruits signaling proteins containing an Src homology 2 domain(s).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Membrane Cholecystokinin-2 Receptor by Agonists Enables Classification of Partial Agonists as Biased Agonists

Magnan

Masri²,

Escrieut

et al. 2011

Journal of Biological Chemistry

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Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of ␤-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or ␤-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and ␤-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser 437 -Xaa 438 -Thr 439 -Thr 440 -Xaa 441 -Ser 442 -Thr 443 ) were critical for ␤-arrestin recruitment. However, this region and ␤-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R⅐␤-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

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The G‐protein‐coupled CCK2 receptor associates with phospholipase Cγ1

Cited by 13 publications

References 23 publications

Role of AMP-18 in oral mucositis

Role of AMP-18 in oral mucositis

Expression of Cholecystokinin-2/Gastrin Receptor in the Murine Pancreas Modulates Cell Adhesion and Cell Differentiation in Vivo

Regulation of Membrane Cholecystokinin-2 Receptor by Agonists Enables Classification of Partial Agonists as Biased Agonists

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