Protein kinase C-mediated tyrosine phosphorylation of paxillin and focal adhesion kinase requires cytoskeletal integrity and is uncoupled to mitogen-activated protein kinase activation in human hepatoma cells

The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) ζ activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCζ regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.

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The Protein Kinase C Inhibitor Go6976 [12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Potentiates Agonist-Induced Mitogen-Activated Protein Kinase Activation through Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor

Molecular Pharmacology ◽

10.1124/mol.104.003533 ◽

2004 ◽

Vol 67 (1) ◽

pp. 184-194 ◽

Cited By ~ 18

Author(s):

Bukhtiar H. Shah ◽

J. Alberto Olivares-Reyes ◽

Kevin J. Catt

Keyword(s):

Epidermal Growth Factor Receptor ◽

Protein Kinase ◽

Growth Factor Receptor ◽

Mitogen Activated Protein Kinase ◽

Kinase Activation ◽

Kinase C ◽

Protein Kinase Activation ◽

Mitogen Activated Protein ◽

Protein Kinase C Inhibitor ◽

Epidermal Growth

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Lipopolysaccharide induces Jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C ζ and phosphatidylcholine-dependent phospholipase C

Blood ◽

10.1182/blood.v96.7.2592 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2592-2598 ◽

Cited By ~ 26

Author(s):

Katarzyna J. Procyk ◽

Maria Rita Rippo ◽

Roberto Testi ◽

Fred Hofmann ◽

Peter J. Parker ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Phospholipase C ◽

Small Gtpases ◽

Mitogen Activated Protein Kinase ◽

Kinase Activation ◽

Kinase C ◽

Mitogen Activated Protein ◽

Pkc Ζ ◽

Phosphoinositide 3 Kinase

Abstract The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) ζ activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCζ regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.

Download Full-text