Regulation of AMP-activated protein kinase activity by G-protein coupled receptors: Potential utility in treatment of diabetes and heart disease

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase nd cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [P32]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 μM PD 098059 (IC50=51 μM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton (“downregulation”) of PKC by a long term (22h) pretreatment with 1 μM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 μM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 μM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [H3]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genisteinsensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.

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Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)98357-2 ◽

1993 ◽

Vol 268 (13) ◽

pp. 9347-9357

Author(s):

M.S. Simonson ◽

W.H. Herman

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

G Protein ◽

Protein Tyrosine Kinase ◽

Kinase Activity ◽

G Protein Coupled Receptors ◽

Tyrosine Kinase Activity ◽

Kinase C ◽

G Protein Coupled ◽

Protein Tyrosine Kinase Activity

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Activation and targeting of mitogen-activated protein kinases by G-protein-coupled receptors

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-045 ◽

2002 ◽

Vol 80 (5) ◽

pp. 375-382 ◽

Cited By ~ 84

Author(s):

Louis M Luttrell

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

G Protein ◽

Map Kinases ◽

Kinase Activity ◽

Nuclear Translocation ◽

G Protein Coupled Receptors ◽

Kinase Activation ◽

Mitogen Activated Protein ◽

G Protein Coupled

Over the past decade, it has become apparent that many G-protein-coupled receptors (GPCRs) generate signals that control cellular differentiation and growth, including stimulation of Ras family GTPases and activation of mitogen-activated protein (MAP) kinase pathways. The mechanisms that GPCRs use to control the activity of MAP kinases vary between receptor and cell type but fall broadly into one of three categories: signals initiated by classical G protein effectors, e.g., protein kinase (PK)A and PKC, signals initiated by cross-talk between GPCRs and classical receptor tyrosine kinases, e.g., "transactivation" of epidermal growth factor (EGF) receptors, and signals initiated by direct interaction between β-arrestins and components of the MAP kinase cascade, e.g., β-arrestin "scaffolds". While each of these pathways results in increased cellular MAP kinase activity, emerging data suggest that they are not functionally redundant. MAP kinase activation occurring via PKC-dependent pathways and EGF receptor transactivation leads to nuclear translocation of the kinase and stimulates cell proliferation, while MAP kinase activation via β-arrestin scaffolds primarily increases cytosolic kinase activity. By controlling the spatial and temporal distribution of MAP kinase activity within the cell, the consequences of GPCR-stimulated MAP kinase activation may be determined by the mechanism by which they are activated.Key words: G-protein-coupled receptor, receptor tyrosine kinase, β-arrestin, mitogen-activated protein kinase, extracellular signal-regulated kinase.

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Composition and Function of G Protein-Coupled Receptor Signalsomes Controlling Mitogen-Activated Protein Kinase Activity

Journal of Molecular Neuroscience ◽

10.1385/jmn:26:2-3:253 ◽

2005 ◽

Vol 26 (2-3) ◽

pp. 253-264 ◽

Cited By ~ 85

Author(s):

Louis M. Luttrell

Keyword(s):

Protein Kinase ◽

G Protein ◽

Kinase Activity ◽

Mitogen Activated Protein Kinase ◽

Protein Kinase Activity ◽

G Protein Coupled Receptor ◽

Mitogen Activated Protein ◽

And Function ◽

G Protein Coupled

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5′-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat

International Journal of Cancer ◽

10.1002/ijc.25558 ◽

2010 ◽

Vol 128 (9) ◽

pp. 2230-2239 ◽

Cited By ~ 29

Author(s):

Taichang Jang ◽

Joy M. Calaoagan ◽

Eunice Kwon ◽

Steven Samuelsson ◽

Lawrence Recht ◽

...

Keyword(s):

Brain Tumor ◽

Protein Kinase ◽

Kinase Activity ◽

Tumor Development ◽

Primary Brain Tumor ◽

Protein Kinase Activity ◽

Amp Activated Protein Kinase

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G-protein-coupled-receptor activation of the smooth muscle calponin gene

Biochemical Journal ◽

10.1042/bj3570587 ◽

2001 ◽

Vol 357 (2) ◽

pp. 587-592 ◽

Cited By ~ 9

Author(s):

Nickolai O. DULIN ◽

Sergei N. ORLOV ◽

Chad M. KITCHEN ◽

Tatyana A. VOYNO-YASENETSKAYA ◽

Joseph M. MIANO

Keyword(s):

Smooth Muscle ◽

Protein Kinase ◽

G Protein ◽

Transcriptional Activation ◽

Fold Increase ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Mitogen Activated Protein Kinase ◽

G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

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