Many peptide hormone and neurotransmitter receptors belonging to the seven membrane-spanning G protein-coupled receptor family have been shown to transmit ligand-dependent mitogenic signals in vitro. However, the physiological roles of the mitogenic activity through G protein-coupled receptors in vivo remain to be elucidated. Here we have generated G protein-coupled cholecystokinin (CCK)-B/ gastrin receptor deficient-mice by gene targeting. The homozygous mice showed a remarkable atrophy of the gastric mucosa macroscopically, even in the presence of severe hypergastrinemia. The atrophy was due to a decrease in parietal cells and chromogranin A-positive enterochromaffin-like cells expressing the H+,K+-ATPase and histidine decarboxylase genes, respectively. Oral administration of a proton pump inhibitor, omeprazole, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophy of the homozygotes. These results clearly demonstrated that the G protein-coupled CCK-B/gastrin receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.Cell proliferation and differentiation are regulated by a wide array of factors such as growth factors, cytokines, and hormones (1). Several peptide hormones such as bombesin/ gastrin-releasing peptide, angiotensin, and endothelin, and neurotransmitters such as serotonin and adrenaline have been shown to stimulate cell proliferation through their own seventransmembrane, heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors in vitro (2-5). Certain serotonin, acetylcholine, or adrenergic receptor subtypes were reported not only to stimulate cell proliferation but also to transform 3T3 fibroblasts in a ligand-dependent manner as do growth factor receptors (3-5). Very recently, G proteincoupled receptors have also been shown to involve tyrosine kinases and the Ras-mitogen-activating protein kinase pathway in their intracellular signaling as do growth factor and cytokine receptors (6-9). Although some peptides could promote the proliferation of a variety of human tumor cell lines in vivo as well as in vitro (10,11), the physiological significance of the mitogenic activity through the G protein-coupled receptor superfamily remains to be clarified.The peptide hormone, gastrin, is well characterized as a stimulant of gastric acid secretion. In addition, there is circumstantial evidence that gastrin presumably functions as a trophic factor for the gastrointestinal tissues (11, 12). Another peptide hormone, cholecystokinin (CCK), is also isolated as a stimulant of enzyme secretion by the pancreas (13). Because of the abundant expression of CCK in the central nervous system as well as in digestive organs, this hormone is also thought to act as a neurotransmitter or modulator in the brain (14). Moreover, the specific receptors for CCK and/or gastrin have been pharmacologically shown to be expressed in various human tumor cells and to stimulat...

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Cholecystokinin (CCK) is an important gastrointestinal hormone as well as a neurotransmitter. Two types of CCK receptors, types A and B, have been identified. The CCK-A receptor is involved in satiety, food intake and behavior, whereas the B receptor is involved in anxiety. We recently produced CCK-A, -B and AB receptor knockout mice to study the role of these receptors in energy metabolism. Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice. Relative liver and kidney weights (g/kg body) were significantly greater in CCK-AR(-/-)BR(-/-) mice than in wild-type mice. Energy metabolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown.

Two closely related casein kinase I (CKI) isoforms, CKI␦ and CKI⑀, are ubiquitously expressed in many human tissues, but their specific biologic function remains to be clarified. Here, we provide the first evidence that CKI⑀ is involved in hematopoietic cell differentiation. CKI⑀, but not CKI␦, was down-regulated along with human granulocytic differentiation. The specific down-regulation was observed in granulocyte colony-stimulating factor (G-CSF)-induced cell differentiation of murine interleukin-3 (IL-3)-dependent myeloid progenitor 32D cells. Introduction of wild-type (WT)- IntroductionMembers of the casein kinase I (CKI) family of monomeric serine/threonine kinases are highly conserved from yeast to human and are ubiquitously expressed in different cell types. 1,2 In mammals, 7 isoforms (␣, ␤, ␥1-3, ␦, and ⑀) have been identified. [3][4][5][6] These isoforms share a high degree of similarity within the NH 2 -terminal catalytic domains but show considerable variation in their carboxy-terminal (C-terminal) noncatalytic domains. Their variable C-terminal domains are responsible for substrate specificity and serve to promote differential subcellular localization of individual isoforms and to modulate kinase activity. 4,[7][8][9][10] Studies of CKI homologs in yeast have shown the biologic role of CKI in the regulation of DNA repair and normal cell cycle progression, vesicular trafficking, and cytokinesis. [11][12][13][14][15] The identification of potential substrates for CKI in vitro also possibly inferred that CKI might be involved in a wide variety of cellular functions in mammals. For example, CKI is likely to regulate DNA and RNA metabolism, cellular morphology, vesicular trafficking, DNA damage response and repair, and the activity of various transmembrane receptors. [16][17][18][19][20][21][22][23][24] From the diverse cellular functions of CKI isoforms arose a possibility that CKI is likely to regulate the stability of their substrates, protein turnover, and transport-dependent cellular processes. [25][26][27][28] However, there have been only a few reports in which the phosphorylation by CKI is shown to be essential for the biologic function of the substrates. Unexpectedly, recent genetic analyses in diverse fields have demonstrated that CKI⑀ plays an essential role in regulating several critical in vivo processes such as circadian rhythm, embryogenesis, and morphogenesis in various species. [29][30][31][32] The homolog of CKI␦ and CKI⑀ was first cloned in a screen for a budding yeast mutant, hrr25. 11 Human CKI␦ and CKI⑀ encoded on 2 independent genes localized at chromosome 17q25 and 22q12-13 are basic polypeptides of 49 kDa and 47 kDa, respectively. 4,5 They are the closest isoforms in the CKI family, because their amino acid sequences are 98% identical over their kinase domains and 53% identical over their C-terminal domains. The autophosphorylation of the C-terminal domain has been shown to inhibit its kinase activity. 33 Successful complementation of hrr25 mutants in budding yeast by human CKI␦ ...