Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases

Abstract

2؉ ] i in the absence of G17. These data demonstrate that the activation state of the MEK1,2/ERK1,2 pathway can modulate the amplitude of the CCK 2 R-mediated Ca 2؉ release response and identify a novel mechanism for cross-talk between EGF receptor-and CCK 2 Rregulated signaling pathways.The gastrointestinal peptide hormone gastrin-(1-17) (G17) 1 plays an essential role in the regulation of digestion by stimulating gastric acid secretion, histamine synthesis and release, and proliferation of the gastric epithelium and endocrine pancreas (1, 2). In cancers of the stomach, pancreas, and colon, G17 promotes tumor cell proliferation, motility, and invasion (3-5). The biological effects of G17 are mediated by the cholecystokinin-2 (CCK 2 )/G17 receptor (CCK 2 R) (previously named CCK-B receptor), a member of the G protein-coupled receptor superfamily. Three splice variants of the CCK 2 R have been identified (6 -8) that bind the structurally related peptides cholecystokinin (CCK) and G17 with high affinities. An early event following agonist activation of CCK 2 R is the phospholipase C␤-mediated elaboration of inositol 1,4,5-triphosphate (6) from membrane phospholipids and the subsequent release of calcium (Ca 2ϩ ) from inositol 1,4,5-triphosphate-sensitive intracellular Ca 2ϩ stores.Calcium is an essential intracellular signal involved in many biological processes including fertilization, secretion, contraction, proliferation, differentiation, and apoptosis (9, 10). Small differences in the amplitude, duration, and/or temporal pattern of change in [Ca 2ϩ ] i can have profound effects on cell physiology, altering programs of gene expression (11, 12), secretory activity (13), cell proliferation, and survival (14 -16). Calcium is an essential signaling molecule in G17-stimulated cell proliferation. In Chinese hamster ovary cells expressing recombinant CCK 2 R, an agonist-induced increase in mitogen-activated protein kinase (MAPK) activity and [ 3 H]thymidine incorporation into DNA requires a slow oscillatory increase in [Ca 2ϩ ] i (17). In the rat pancreatic cancer cell line AR4-2J, a CCK 2 Rmediated increase in [Ca 2ϩ ] i is required for formation of the Shc-Grb2-Sos protein complex and subsequent activation of MAPK (18). Defining the molecular mechanisms involved in CCK 2 R regulation of [Ca 2ϩ ] i is necessary to understand the proliferative effects of G17 on normal and neoplastic cells.Like G17, epidermal growth factor (EGF) also stimulates the proliferation of gastric epithelial cells (19,20), and recently, the G17-related peptide CCK has been shown to synergize with EGF to stimulate DNA synthesis ([ 3 H]thymidine incorporation), cyclin-D3 expression, and retinoblastoma protein phosphorylation in cells expressing both CCK 2 R and EGF receptors (21). EGF and the related growth factors transforming growth factor-␣ and amphiregulin bind to a family of receptors known as type I receptor tyrosine kinases. This family is composed of four related receptors: the EGF receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 ...

Epidermal Growth Factor Induces WISP-2/CCN5 Expression in Estrogen Receptor-α-Positive Breast Tumor Cells through Multiple Molecular Cross-talks

“…Because EGF exerts its physiologic and pathophysiologic effects through its tyrosine kinase receptor, EGFR/HER-1, by activating multiple signal transduction pathways (16,17,30,55,56), we used several standard approaches to explore whether analogous signaling pathways were involved in the regulation of WISP-2/CCN5 expression by EGF. The studies have shown that EGFR/HER-1 mediates the action of EGF because up-regulation of WISP-2/CCN5 mRNA in MCF-7 cells by EGF could be inhibited by either EGFR-specific siRNA or EGFR-specific tyrosine kinase inhibitor AG30 (Figs.…”

“…Multiple signal transduction pathways, including Src, Ras, Raf, mitogen-activated protein kinase (MAPK) kinase, c-Jun NH 2 -terminal kinase, and protein kinase C pathways, are involved in EGF-EGFR-induced transcriptional activations of various genes during physiologic and pathophysiologic needs (23,(29)(30)(31)(32). Moreover, estrogen, through its membrane receptor, rapidly activates several downstream signaling cascades that may eventually trigger the cross-talk between ER and EGFR, which in turn leads to activation of several signal transduction pathways and genes required to alter the cell biology of breast cancer (23,33).…”

Calcium handling in porcine coronary endothelial cells by gastrin-17

“…In addition, involvement of MEK1/2 and ERK1/2 pathways has been reported (Olszewska-Pazdrak et al 2004). Thus, with the above considerations and as an extension of earlier works from our group showing an effect of gastrin-17 on NO production, the aim of this study was to investigate in PCAEC the effects of gastrin-17 on [Ca 2C ] c handling and the mechanisms involved.…”

“…Changes of [Ca 2C ] c have been reported to be also crucial for the response of gastrointestinal cells to CCK receptor agonists. Hence, Ca 2C is an essential signalling molecule in gastrin-17-stimulated cell proliferation (Olszewska-Pazdrak et al 2004) and is involved in gastrin-induced histamine secretion (Shibata et al 2006). In addition, in isolated pig parietal cells, both gastrin-17 and the synthetic peptide pentagastrin increased [Ca 2C ] c in a dose-dependent manner (Cabero et al 1989).…”

“…Also, the CCK receptor agonists, CCK58 and CCK8, have been found to either cause transient oscillatory [Ca 2C ] c increases or sustained responses depending on whether CCK receptor agonists were used in physiological or supraphysiological concentrations in murine isolated pancreatic acinar cells (Criddle et al 2009). The above effects on Ca 2C movements have been generally reported to be related to either Ca 2C entry from the extracellular space through CCK receptor stimulation (Criddle et al 2009) and/or PKC and IP3-dependent opening of intracellular stores (Zanner et al 2002, Olszewska-Pazdrak et al 2004). …”