Platelet-derived growth factor activates protein kinase C epsilon through redundant and independent signaling pathways involving phospholipase C gamma or phosphatidylinositol 3-kinase.

Leptin-deficient Lepob/Lepob mice hypersecrete insulin in response to acetylcholine stimulation of the phospholipase C-protein kinase C (PLC-PKC) pathway, and leptin constrains this hypersecretion. Leptin has been reported to activate phosphatidylinositol 3-kinase (PI 3-K) and subsequently phosphodiesterase (PDE) to impair protein kinase A (PKA)-induced insulin secretion from cultured islets of neonatal rats. We determined if PKA-induced insulin secretion was also hyperresponsive in Islets from Lepob/Lepob mice, and if leptin impaired this pathway in islets from these mice. Additionally, the possible role for PI 3-K and PDE in leptin-induced control of acetylcholine-induced insulin secretion was examined. Stimulation of Insulin secretion with GLP-1, forskolin (an activator of adenylyl cyclase), or IBMX (an inhibitor of PDE) did not cause hypersecretion of insulin from islets of young Lepob/Lepob mice, and leptin did not inhibit GLP-1-induced insulin secretion from islets of these mice. Inhibition of PDE with IBMX also did not block leptin-induced inhibition of acetylcholine-mediated insulin secretion from islets of Lepob/Lepob mice. But, preincubation of islets with wortmannin, an Inhibitor of PI 3-K activity, blocked the ability of leptin to constrain acetylcholine-induced insulin secretion from islets of Lepob/Lepob mice. We conclude that the capacity of the PKA pathway to stimulate insulin secretion is not increased in islets from young Lepob/Lepob mice, and that leptin does not regulate this pathway in islets from mice. Leptin may stimulate PI 3-K to constrain PLC-PKC-induced insulin secretion from Islets of Lepob/Lepob mice.

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Protein kinase C modulates negatively the hepatocyte growth factor-induced migration, integrin expression and phosphatidylinositol 3-kinase activation

Cellular Signalling ◽

10.1016/j.cellsig.2003.09.009 ◽

2004 ◽

Vol 16 (4) ◽

pp. 505-513 ◽

Cited By ~ 6

Author(s):

Annamária Gujdár ◽

Szabolcs Sipeki ◽

Erzsébet Bander ◽

László Buday ◽

Anna Faragó

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Hepatocyte Growth Factor ◽

Integrin Expression ◽

Phosphatidylinositol 3 Kinase ◽

Kinase Activation ◽

Kinase C ◽

Hepatocyte Growth ◽

Phosphatidylinositol 3

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Phosphatidylinositol 3-Kinase Is a Requirement for Insulin-Like Growth Factor I-Induced Differentiation, but not for Mitogenesis, in Fetal Brown Adipocytes

Molecular Endocrinology ◽

10.1210/mend.11.5.9924 ◽

1997 ◽

Vol 11 (5) ◽

pp. 595-607 ◽

Cited By ~ 35

Author(s):

Angela M. Valverde ◽

Margarita Lorenzo ◽

Paloma Navarro ◽

Manuel Benito

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Signaling Pathways ◽

Brown Adipocyte ◽

Phosphatidylinositol 3 Kinase ◽

Brown Adipocytes ◽

Factor I ◽

Kinase C ◽

Igf I

Abstract In the present study we have examined the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the insulin-like growth factor I (IGF-I)-signaling pathways involved in differentiation and in mitogenesis in fetal rat brown adipocytes. Activation of PI 3-kinase in response to IGF-I was markedly inhibited by two PI 3-kinase inhibitors (wortmannin and LY294002) in a dose-dependent manner. IGF-I-stimulated glucose uptake was also inhibited by both compounds. The expression of adipogenic-related genes such as fatty acid synthase, malic enzyme, glycerol 3-phosphate dehydrogenase, and acetylcoenzyme A carboxylase induced by IGF-I was totally prevented in the presence of IGF-I and any of those inhibitors, resulting in a marked decrease of the cytoplasmic lipid content. Moreover, the expression of the thermogenic marker uncoupling protein induced by IGF-I was also down-regulated in the presence of wortmannin/LY294002. IGF-I-induced adipogenic- and thermogenic-related gene expression was only partly inhibited by the p70S6k inhibitor rapamycin. In addition, pretreatment of brown adipocytes with either wortmannin or LY294002, but not with rapamycin, blocked protein kinase C ζ activation by IGF-I. In contrast, IGF-I-induced fetal brown adipocyte proliferation was PI 3-kinase-independent. Our results show for the first time an essential requirement of PI 3-kinase in the IGF-I-signaling pathways leading to fetal brown adipocyte differentiation, but not leading to mitogenesis. In addition, protein kinase C ζ seems to be a signaling molecule also involved in the IGF-I differentiation pathways downstream from PI 3-kinase.

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Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-ζ and Raf-1

Biochemical Journal ◽

10.1042/bj3250303 ◽

1997 ◽

Vol 325 (2) ◽

pp. 303-307 ◽

Cited By ~ 50

Author(s):

Marc C. M. VAN DIJK ◽

Henk HILKMANN ◽

Wim J. VAN BLITTERSWIJK

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Phospholipase C ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Platelet Derived Growth Factor ◽

Kinase C ◽

Mitogen Activated Protein ◽

Pkc Ζ

The mechanism of Raf-1 activation by platelet-derived growth factor (PDGF) is poorly defined. We previously reported that, in Rat-1 fibroblasts, PDGF activates a phosphatidylcholine-specific phospholipase C (PC-PLC) and that the product, diacylglycerol, somehow activates protein kinase C-ζ (PKC-ζ). Both PC-PLC and PKC-ζ activities were required for PDGF activation of mitogen-activated protein kinase (MAPK). Now we report that MAPK activation by exogenous PC-PLC depends on Raf-1 activation. PKC-ζ co-immunoprecipitates with, phoshorylates and activates Raf-1, suggesting that in the PDGF- and PC-PLC-activated MAPK pathway, PKC-ζ operates in a signalling complex as a direct activator of Raf-1.

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