Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of epidermal growth factor (EGF) on the metabolism of phosphatidylinositol were examined using A431 cells labeled with either 32PO3(4)- or myo-[3H] inositol. EGF was found to increase the incorporation of phosphate into phosphatidic acid, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-diphosphate as early as 15 s after addition of hormone. These changes were found to be due to two effects of EGF on the phosphatidylinositol cycle. First, EGF stimulated the breakdown of phosphatidylinositol 4,5-diphosphate to diacylglycerol and an inositol triphosphate. In addition, EGF induced a rise in the levels of phosphatidylinositol 4-monophosphate. The EGF-dependent increases in both inositol triphosphate production and phosphatidylinositol 4-monophosphate levels were inhibited by pretreatment of the cells with 12-O-tetradecanoylphorbol-13-acetate. Treatment of the cells with pertussis toxin did not inhibit either of these responses. However, treatment of the cells with cholera toxin selectively abolished the ability of EGF to stimulate the rise in phosphatidylinositol monophosphate levels but did not alter the ability of the hormone to induce the breakdown of phosphatidylinositol diphosphate. The effects of cholera toxin were not mimicked by forskolin, cAMP analogs, or isobutyl-methylxanthine. These data demonstrate that EGF stimulates the production of inositol triphosphate. In addition, the findings are consistent with the hypothesis that EGF independently stimulates a phosphatidylinositol kinase. Based on the effects of cholera toxin and the inability of cyclic nucleotides to mimic this response, the effect of EGF on the phosphatidylinositol kinase may be mediated via a guanine nucleotide-binding protein that is not involved in cAMP production.
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PMID:Epidermal growth factor stimulates the production of phosphatidylinositol monophosphate and the breakdown of polyphosphoinositides in A431 cells. 243 85

The calcium-sensing receptor (CaR) is a G protein-coupled receptor that regulates physiological processes including Ca(2+) metabolism, Na(+), Cl(-), K(+), and H(2)0 balance, and the growth of some epithelial cells through diverse signaling pathways. Although many effects of CaR are mediated by the heterotrimeric G proteins Galpha(q) and Galpha(i), not all signaling pathways regulated by CaR have been identified. We used human embryonic kidney (HEK)-293 cells that stably express human CaR to study the regulation of inositol lipid metabolism by CaR. The nonfunctional mutant CaR(R796W) was used as a negative control. We found that CaR regulates phosphatidylinositol (PI) 4-kinase, the first step in inositol lipid biosynthesis. In cells pretreated with to inhibit phospholipase C activation and to block the degradation of PI 4,5-bisphosphate to form [(3)H]inositol trisphosphate (IP(3)), CaR stimulated the accumulation of [(3)H]PI monophosphate (PIP). Additionally, wortmannin, an inhibitor of both PI 3-kinase and type III PI 4-kinase, blocked CaR-stimulated accumulation of [(3)H]PIP and inhibited [(3)H]IP(3) production. CaR-stimulated inositol lipid synthesis was attributable to PI 4-kinase and not PI 3-kinase because CaR did not activate Akt, a downstream target of PI 3-kinase. CaR associates with PI 4-kinase based on the findings that CaR and the 110-kDa PI 4-kinase beta can be co-immunoprecipitated with antibodies against either CaR or PI 4-kinase. The PI-4 kinase in co-immunoprecipitates with anti-CaR antibody was activated in Ca(2+)-stimulated HEK-293 cells, which stably express the wild type CaR. Pertussis toxin did not affect the formation of [(3)H]IP(3) or the rise in intracellular Ca(2+) (Handlogten, M. E., Huang, C. F., Shiraishi, N., Awata, H., and Miller, R. T. (2001) J. Biol. Chem. 276, 13941-13948). RGS4, an accelerator of GTPase activity of members of the Galpha(i) and Galpha(q) families, attenuated the CaR-stimulated PLC activation and IP(3) accumulation, which is mediated by Galpha(q), but did not inhibit CaR-stimulated [(3)H]PIP formation. In HEK-293 cells, which express wild type CaR, Rho was enriched in immune complexes co-immunoprecipitated with the anti-CaR antibody. C(3) toxin, an inhibitor of Rho, also inhibited the CaR-stimulated [(3)H]IP(3) production but did not lead to CaR-stimulated [(3)H]PIP formation, reflecting inhibition of PI 4-kinase. Taken together, our data demonstrate that CaR stimulates PI 4-kinase, the first step in inositol lipid biosynthesis conversion of PI to PI 4-P by Rho-dependent and Galpha(q)- and Galpha(i)-independent pathways.
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PMID:Parallel activation of phosphatidylinositol 4-kinase and phospholipase C by the extracellular calcium-sensing receptor. 1190 35