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      Noradrenaline-Induced Paxillin Phosphorylation, ERK Activation and MEK-Regulated Contraction in Intact Rat Mesenteric Arteries

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          In rat mesenteric arteries, noradrenaline (NA) induces a time-dependent increase in tyrosine phosphorylation of a number of proteins, one of which was identified as paxillin. NA-induced protein tyrosine phosphorylation was ablated by tyrosine kinase inhibition, virtually unaffected by protein kinase C (PKC) inhibition or PKC downregulation and was mimicked by KCl. NA also caused a time-dependent activation of the extracellular signal-regulated kinases (ERK)1 and ERK2. These responses were blocked by the ERK-activating kinase (MEK) inhibitor PD98059 and by tyrosine kinase inhibition but only modestly attenuated by PKC downregulation or inhibition. Pretreatment of cannulated mesenteric arteries (50 mm Hg internal pressure) with PD98059 significantly reduced the contractile responsiveness of the vessels to NA (1.56 ± 0.14 µ M, EC<sub>50</sub> control; 3.32 ± 0.49 µ M, EC<sub>50</sub> + PD98059, p < 0.01). Thus, NA induces time-dependent increases in protein-tyrosine phosphorylation and ERK activation in rat mesenteric arteries that could suggest a role for Ca<sup>2+</sup>-dependent non-receptor tyrosine kinases and ERKs in the response of small arteries to NA. In addition, the modulation of NA-induced mesenteric artery contraction by inhibition of the MEK/ERK pathway further implicates ERK in the regulation of, though perhaps not the mediation of NA-induced small artery contraction.

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          Most cited references 11

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          Protein kinase C alpha activates RAF-1 by direct phosphorylation.

           U Rapp,  D Marmé,  H Vahidi (1993)
          The kinase Raf-1 can be activated by treatment of cells with mitogens and by the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) (reviewed in refs 1,2). Activated Raf-1 triggers a protein kinase cascade by direct phosphorylation of MAP kinase kinase, resulting in phosphorylation of ternary complex factor and Jun by MAP kinase. Here we investigate the molecular mechanism and biological consequences of PKC alpha-mediated Raf-1 activation in NIH3T3 fibroblasts. PKC alpha directly phosphorylates and activates Raf-1 both in vitro and in vivo. PKC alpha induces Raf-1 phosphorylation at several sites, including a serine residue at position 499. Mutation of serine at this position or at residue 259 does not abrogate Raf-1 stimulation by a combination of Ras plus the src tyrosine kinase Lck, but severely impedes Raf-1 activation by PKC alpha. Consistent with such a direct interaction is the observation that Raf-1 and PKC alpha cooperate in the transformation of NIH3T3 cells. The Ser499 phosphorylation site is necessary for this synergism.
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            Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf.

             S Hirai,  K Mizuno,  Y. Ueda (1996)
            Although the involvement of protein kinase C (PKC) in the activation of the mitogen-activated protein (MAP) kinase pathway has been implicated through experiments using 12-O-tetradecanoylphorbol-13-acetate (TPA), there has been no direct demonstration that PKC activates the MAP kinase pathway. A Raf-dependent intact cell assay system for monitoring the activation of MAPK/ERK kinase (MEK) and extracellular signal-related kinase (ERK) permitted us to evaluate the role of PKC isotypes in MAP kinase activation. Treatment of cells with TPA or epidermal growth factor resulted in the activation of MEK and ERK. The activation of the MAP kinase pathway triggered by epidermal growth factor was completely inhibited by dominant-negative Ras (RasN17), whereas the activation triggered by TPA was not, consistent with previous observations. The introduction of an activated point mutant of PKCdelta, but not PKCalpha or PKCepsilon, resulted in the activation of the MAP kinase pathway. The activation of MEK and ERK by an activated form of PKCdelta requires the presence of c-Raf and is independent of RasN17. These results demonstrate that activation of PKCdelta is sufficient for the activation of MEK and ERK and that the pathway operates in a manner dependent on c-Raf and independent of Ras.
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              How MAP Kinases Are Regulated


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2002
                13 February 2002
                : 39
                : 1
                : 1-11
                aSchool of Biological Sciences, University of Manchester, and bDepartment of Medicine, Manchester Royal Infirmary, Manchester, UK
                48988 J Vasc Res 2002;39:1–11
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 4, References: 39, Pages: 11
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