Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the renal medulla during antidiuresis, the extracellular fluid becomes hyperosmotic. Madin-Darby canine kidney (MDCK) epithelial cells adapt in hyperosmotic conditions and serve as a useful tissue culture model for cellular responses to hyperosmolality. We demonstrate that hyperosmolality stimulates phospholipase C, Raf-1 kinase mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase activities and that it increases phosphorylation of Raf-1 kinase, and p42 MAP kinase in MDCK cells. Stimulation of these kinases is osmolality-dependent (from 300 to 600 mosm/kg H2O). The time course of activation is sequential; the peak stimulation for Raf-1 kinase is at 5 min, at 10 min for MAP kinase kinase and MAP kinase, and at 20 min for S6 kinase. The activation of Raf-1 kinase and MAP kinase is inhibited by phorbol 12-myristate 13-acetate pretreatment in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein, herbimycin) do not significantly suppress hyperosmolality-induced MAP kinase activity. The increase of Ins-1,4,5-P3 levels by hyperosmolality suggests that activation of these kinases is mediated at least partially via activation of phospholipase C. Thus, hyperosmolality stimulates the serine/threonine kinases, Raf-1 kinase, MAP kinase kinase, MAP kinase, and S6 kinase, via predominantly protein kinase C-dependent, tyrosine kinase-independent pathways in MDCK cells.
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PMID:Sequential activation of Raf-1 kinase, mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase by hyperosmolality in renal cells. 752 42

Protein kinase C (PKC) has been reported to be associated with the activation of extracellular signal-regulated kinase (ERK) by hyperosmolality. However, it is unclear whether hyperosmolality induces PKC activation and which PKC isoforms are involved in ERK activation. In this study, we demonstrate that NaCl increases total PKC activity and induces PKCalpha, PKCdelta, and PKCepsilon translocation from the cytosol to the membrane in NIH/3T3 cells, suggesting that hyperosmotic stress activates conventional PKC (cPKC) and novel PKC (nPKC). Further studies show that NaCl-inducible ERK1 and ERK2 (ERK1/2) activation is a consequence of cPKC and nPKC activation, because either downregulation with 12-O-tetradecanoylphorbol 13-acetate or selective inhibition of cPKC and nPKC by GF-109203X and rottlerin largely inhibited the stimulation of ERK1/2 phosphorylation by NaCl. In addition, we show that NaCl increases diacylglycerol (DAG) levels and that a phospholipase C (PLC) inhibitor, U-73122, inhibits NaCl-induced ERK1/2 phosphorylation. These results, together, suggest that a hyperosmotic NaCl-induced signaling pathway that leads to activation of ERK1/2 may sequentially involve PLC activation, DAG release, and cPKC and nPKC activation.
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PMID:Hyperosmolality induces activation of cPKC and nPKC, a requirement for ERK1/2 activation in NIH/3T3 cells. 1064 17