Effect of Sulfation of CCK-8 on Its Stimulation of the Endocrine and Exocrine Secretion from the Isolated Perfused Porcine Pancreas

Jensen, Steen Lund; Hoist, Jens; Nielsen, O.B.; Rehfeld, Jens F.

doi:10.1159/000198675

Cited by 25 publications

(10 citation statements)

References 11 publications

(16 reference statements)

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“…This observation is in agreement with the previous reports that the sulphate group of CCK 8 SO 4 interacts directly with Met195 and Arg197 of the CCK1 receptor [24, 25], and with either Arg57 and Tyr61 [26], or His 207 and Arg 208 [27], of the CCK2 receptor. We conclude that enhancement by metal binding is not the explanation for the previous observation that sulphation of CCK 8 increases CCK1 receptor binding and biological activity [8]. …”

Section: Resultscontrasting

confidence: 68%

“…CCK, which was originally isolated as a 33-residue peptide from the mucosa of the gastrointestinal tract, is responsible for gallbladder contraction and pancreatic enzyme secretion, and also functions as a neurotransmitter in the central nervous system [7]. Truncation of the N-terminal end of CCK 33 to CCK 8 occurs naturally, and has no effect on immunoreactivity or bioactivity, but sulphation on the sole tyrosine residue greatly increases receptor binding and biological potency [8]. CCK is structurally and functionally related to the gastric peptide hormone gastrin (ZGPWLEEEEEAYGWMDFamide), with which it shares a common amidated C-terminal pentapeptide.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine modification enhances metal-ion binding

Baldwin

Bailey

Shehan

et al. 2008

Biochemical Journal

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Tyrosine sulphation is a common modification of many proteins, and the ability to phosphorylate tyrosine residues is an intrinsic property of many growth factor receptors. We have utilized the peptide hormone cholecystokinin (CCK8), which occurs naturally in both sulphated and unsulphated forms, as a model to investigate the effect of tyrosine modification on metal ion binding. The changes in absorbance and fluorescence emission on Fe3+ ion binding indicated that tyrosine sulphation or phosphorylation increased the stoichiometry from 1 to 2, without greatly affecting the affinity (0.6–2.8 μM at pH 6.5). Measurement of calcium binding with a calcium-selective electrode revealed that phosphorylated CCK8 bound two Ca2+ ions. CCK8 and sulphated CCK8 each bound only one Ca2+ ion with lower affinity. Binding of Ca2+, Zn2+ or Bi3+ ions to phosphorylated CCK8 did not cause any change in absorbance, but substantially increased the change in absorbance on subsequent addition of Fe3+ ions. Our results demonstrate that tyrosine modification may increase the affinity of metal ion binding to peptides, and imply that metal ions may directly regulate many signaling pathways.

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Section: Resultscontrasting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Tyrosine modification enhances metal-ion binding

Baldwin

Bailey

Shehan

et al. 2008

Biochemical Journal

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“…58 Gastrin exhibits a higher binding affinity for the CCK-B receptor than for the CCK-A receptor, whereas CCK is a high affinity agonist for both the CCK-A and CCK-B receptors. 59 Human pancreatic cancer cell lines secrete gastrin, and the expression of gastrin directly correlates with their growth rate in vivo. 60 Since gastrin is expressed in the fetal pancreas but not adult pancreas 61 and is re-expressed in early stage human PanINs, 62 our discovery of expression of the CCK-B receptor to which gastrin binds, may provide new insights to the etiology of pancreatic cancer development.…”

Section: Discussionmentioning

confidence: 99%

Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

Smith¹,

Cooper²,

McGovern³

et al. 2014

Pancreas

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Objectives Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved with the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK-receptor antagonist (proglumide, 0.1mg/ml). Pancreas from mice were removed and examined histologically for number and grade of PanINs after 1, 2 or 4 months of antagonist therapy. Results Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed and progression to advanced lesions arrested in mice treated with proglumide compared to controls (p=0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared to vehicle (pitalic>0.001). Conclusions These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. Use of CCK-receptor antagonists may have a role in cancer prophylaxis in high risk subjects, and may reduce fibrosis in the microenvironment.

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“…However, its possible role in intracellular traffic signalling and as a protective mechanism against oxidation of tyrosine has been suggested [16,17]. In Table 3 Tyr the case of some peptides such as cholecystokinin [18], phyllokinin [19] and leucosulfakinin [20], sulfation of specific tyrosine residue(s) was found to augment dramatically the bioactivity of the peptide. Sulfation of tyrosine residues has been shown to make gastrin a pancreatic secretogog [21].…”

Section: Resultsmentioning

confidence: 99%

Presence of tyrosine‐O‐sulfate in sheep pituitary prolactin

1988

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When the metabolically obtained 3sS-labelled sheep pituitary prolaetin-rich fraction was subjected to chemical deglycosylation the radioactivity was retained in the immunoprecipitable prolactin. 35S-labelled prolactin-fich pituitary extract was fractionated on SDS-PAGE and protein was extracted from prolactin positive bands. When the extracted 3sS-labelled prolactin was hydrolysed by alkali and then chromatographed on a thin layer of silica, it showed the presence of a radioactive compound which had an Rf value identical to the standard Tyr-O-SO 4 synthesized and characterized in our laboratory.

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Effect of Sulfation of CCK-8 on Its Stimulation of the Endocrine and Exocrine Secretion from the Isolated Perfused Porcine Pancreas

Cited by 25 publications

References 11 publications

Tyrosine modification enhances metal-ion binding

Tyrosine modification enhances metal-ion binding

Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

Presence of tyrosine‐O‐sulfate in sheep pituitary prolactin

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