The cholecytostokinin-2 receptor (CCK2R) shows growth-promoting effects on normal and neoplastic gastrointestinal cells when stimulated by gastrin. It is highly expressed in many cancers of different origins including medullary thyroid carcinomas, small cell lung cancers, astrocytomas, and ovarian cancers but is not present in the corresponding tissues.40 A constitutively active CCK2R mutant in which the conserved glutamate (E) within the (E)-aspartate (D)-arginine (R)-tyrosine (Y)
motif (E/DRY motif) was replaced by alanine (A) appeared to have high tumorigenic potential. Injection of NIH 3T3 cells expressing this CAM receptor resulted in the development of rapidly growing tumors.41 Interestingly, a splice variant of CCK2R isolated from human colorectal cancer contained 69 additional amino acids in the third intracellular loop. This mutant receptor was shown to constitutively activate proliferative signaling pathways including Src tyrosine kinases, suggesting a link between the constitutive activity of this mutant receptor and the development of colorectal cancer.42
Expression by transgenic mice of the human CCK2R specifically in pancreatic exocrine cells and stimulation of the receptor induces growth of the pancreas.43 Moreover, expression of the CCK2 receptor in pancreatic cells over time results in the development of tumors, suggesting a role of CCK2 receptors in the initiation of pancreatic cancer.4344
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