High tumorigenic potential of a constitutively active mutant of the cholecystokinin 2 receptor.
The cholecystokinin 2 receptor (CCK2R) increases proliferation of normal and neoplastic gastrointestinal cells and activates various mitogenic signaling pathways when stimulated by gastrin. To study the incidence of permanent activation of this receptor in tumorigenicity, a constitutively active mutant was generated by replacing residue Glu151 in the conserved E/DRY motif by Ala. Expression of the E151A-CCK2R mutant in NIH-3T3 cells causes ligand-independent activation of phospholipase C and ornithine decarboxylase, two enzymes critical for mitogenesis. Strikingly, the constitutive activity of this mutant was associated with dramatic alteration of NIH-3T3 cell morphology, enhanced cell proliferation and invasion. Moreover, injection of cells expressing E151A-CCK2R in nude mice resulted in the development of large and rapidly growing tumors. By contrast, none of these effects was observed with cells expressing the wild-type CCK2R, indicating that the tumorigenic properties of the E151A-CCK2R mutant is the result of its constitutive activation. To date, this is the first report that provides evidence for the high tumorigenic effect of a constitutively active CCK2R mutant, thus raising a potential role of the CCK2R in human cancer.
Galés
Céline
C
INSERM U531, Institut Louis Bugnard, CHU Rangueil, 31403 Toulouse Cedex, France.
Sanchez
Didier
D
Poirot
Marc
M
Pyronnet
Stéphane
S
Buscail
Louis
L
Cussac
Daniel
D
Pradayrol
Lucien
L
Fourmy
Daniel
D
Silvente-Poirot
Sandrine
S
D016475:3T3 Cells / Q000473:pathology; D000409:Alanine / Q000235:genetics; D020816:Amino Acid Motifs; D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009955:Ornithine Decarboxylase / Q000378:metabolism; D017354:Point Mutation; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000235:genetics* / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D018698:Glutamic Acid; D010738:Type C Phospholipases; D009955:Ornithine Decarboxylase; D000409:Alanine