Intracellular Signaling by Hydrolysis of Phospholipids and Activation of Protein Kinase C

Nishizuka, Yasutomi

doi:10.1126/science.1411571

Cited by 4,335 publications

(2,930 citation statements)

References 189 publications

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“…The administration of the PKC inhibitor also shifted to the left the dose-response curve of physostigmine. Furthermore, activation of PKC by phorbol esters, such as PMA and PDBu (Nishizuka, 1992), dose-dependently prevented the physostigmine and oxotremorine increase of pain threshold. These data clearly indicate that activation of PKC by cholinomimetics constitutes a significant pathway involved in negative modulation of central muscarinic antinociceptive response.…”

Section: Discussionmentioning

confidence: 91%

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

Galeotti¹,

Bartolini²,

Ghelardini³

2002

Neuropsychopharmacol

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The cellular events involved in muscarinic analgesia were investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with antisense oligonucleotides (aODNs) against the a subunit of G q and G 11 proteins prevented the analgesia induced by physostigmine and oxotremorine. Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as well as the injection of an aODN complementary to the sequence of PLCb 1 , antagonized the increase of the pain threshold induced by both cholinomimetic drugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP 3 receptor antagonist, the antinociception induced by physostigmine and oxotremorine was dose-dependently antagonized. I.c.v. pretreatment with TMB-8, a blocker of Ca 2+ release from intracellular stores, prevented the increase of pain threshold induced by the investigated cholinomimetic drugs. Coadministration of Ca 2+ restored the muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor calphostin C, resulted in a dose-dependent enhancement of physostigmine-and oxotremorine-induced antinociception. The administration of PKC activators, such as PMA and PDBu, dose dependently prevented the cholinomimetic drug-induced increase of pain threshold. Neither aODNs nor pharmacological treatments employed produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC-IP 3 pathway in central muscarinic analgesia in mice. Furthermore, activation of PKC by cholinomimetic drugs may represent a pathway of negative modulation of muscarinic antinociception.

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Section: Discussionmentioning

confidence: 91%

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

Galeotti¹,

Bartolini²,

Ghelardini³

2002

Neuropsychopharmacol

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“…IP3 then stimulates the opening of Ca 2 þ channels and increases the cytoplasmic concentration of Ca 2 þ . DAG and Ca 2 þ , along with other cofactors, lead to the activation of classic PKCs (Nishizuka, 1992;Parker and Murray-Rust, 2004). One possible mechanism of PKCa activation by ErbB2 is that ErbB2 phosphorylates and associates with PLCg and leads to PKC activation (Peles et al, 1991).…”

Section: Erbb2 Activates Pkca Through Src Kinasementioning

confidence: 99%

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Tan

Sun

et al. 2006

Oncogene

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Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. a-Isozyme of protein kinase C (PKCa), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCa in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCa and determined what role PKCa plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCa and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCa in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCa membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCa is co-immunoprecipitated with Src and PKCa expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominantnegative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCa inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCa is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCa and Src inhibitor clinical trials.

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“…5 Protein kinase C enzymes are a family of serine/ threonine kinases that play a major role in signal transduction and contribute to the regulation of cellular differentiation and proliferation. 6 Protein kinase C-beta I (PKC-beta I) and beta II are the two major isoforms expressed in B-lymphocytes. 7 The RNA expression of both isoforms has been studied in patients with DLBCL, and it seems to be associated with a bad outcome both within the Lymphochip and Affymetrix data sets.…”

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confidence: 99%

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

et al. 2007

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Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKCbeta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in highrisk patients (14 vs 58%, Po0.001) and in those with PKC-beta II positivity (36 vs 49%, P ¼ 0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P ¼ 0.033) and a worse 5-year EFS (48 vs 66%, P ¼ 0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio ¼ 1.68, P ¼ 0.037) and the IPI (HR ¼ 3.07, Po0.001) were independent poor prognostic factors. PKCbeta II (HR ¼ 1.72, P ¼ 0.046) and the IPI (HR ¼ 5.16, Po0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.

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Intracellular Signaling by Hydrolysis of Phospholipids and Activation of Protein Kinase C

Cited by 4,335 publications

References 189 publications

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma

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