c-Jun NH(2)-terminal kinase pathway in growth-promoting effect of the G protein-coupled receptor cholecystokinin B receptor: a protein kinase C/Src-dependent-mechanism.
The proliferative effects of gastrin on normal and malignant gastrointestinal tissues have been shown to be mediated by a G protein-coupled receptor (GPCR), the cholecystokinin B receptor. The c-Jun NH(2)-terminal kinase (JNK) pathway has been implicated in the regulation of mitogenesis by growth factors or cytokines. However, the contribution of this signaling cascade to the proliferative effects of GPCR remains largely unknown. Here, we show that cholecystokinin B receptor occupancy by gastrin leads to the activation of the JNK pathway. The mechanism involves certain protein kinase C isoforms and Src family kinases other than p60Src. The complex p130Cas/CrkII, known to be involved in JNK activation, is also activated in response to gastrin by a protein kinase C- and Src-dependent mechanism. However, gastrin-induced CrkII and JNK pathways are independent. Using a dominant negative mutant of c-Jun, we blocked the ability of gastrin to induce DNA synthesis, demonstrating a major role of the JNK pathway in the growth-promoting effect of a GPCR agonist.
INSERM U.531, Groupe de Recherche de Biologie et Pathologie Digestives, Institut Louis Bugnard, Bat. L3, 31403 Toulouse, France.
Stephanie
S
Dehez
Christiane
C
Bierkamp
Aline
A
Kowalski-Chauvel
Laurence
L
Daulhac
Chantal
C
Escrieut
Christiane
C
Susini
Lucien
L
Pradayrol
Daniel
D
Fourmy
Catherine
C
Seva
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000502:physiology*; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130; D019061:src-Family Kinases / Q000378:metabolism*
D005755:Gastrins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D050717:Retinoblastoma-Like Protein p130; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins