Synergistic Induction of Mitogen-Activated Protein Kinase Phosphatase-1 by Thrombin and Epidermal Growth Factor Requires Vascular Endothelial Growth Factor Receptor-2

Chandrasekharan, Unni M.; Waitkus, Matthew S.; Kinney, Corttrell M.; Walters-Stewart, Alicia; DiCorleto, Paul E.

doi:10.1161/atvbaha.110.212399

Cited by 14 publications

(16 citation statements)

References 29 publications

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“…Previous work from our laboratory demonstrated that simultaneous stimulation of EC with EGF and TRAP caused a significant increase in EC transwell migration in vitro (7). We observed a similar synergistic increase in migration when an EC monolayer was mechanically wounded and then treated with EGF, TRAP, or both for 16 h (Fig.…”

Section: Inhibition Of Akt Is Required For Stat3 Ser 727 Phosphorylatsupporting

confidence: 81%

“…ERK) and cellular outcomes (e.g. gene expression, migration, and angiogenesis) appears to be much weaker than more potent agonists like EGF and VEGF (7,65). Our results show for the first time that perhaps one of the strongest responses elicited by PAR-1 signaling is a modulation of EGF-induced PI3K-AKT signaling and a triggering of STAT3-dependent gene expression.…”

Section: Discussionmentioning

confidence: 69%

“…In this manner, signaling interactions enable cells to process disparate extracellular information at downstream signaling nodes and formulate appropriate biological responses based on specific combinations of signaling inputs (3,4). Crosstalk is an important factor in a number of biological processes, including cellular migration (5), proliferation (6), gene expression (7,8), and calcium influx (4). However, the specific molecular mechanisms by which cells integrate signals from multiple cell surface receptors are poorly understood (1).…”

mentioning

confidence: 99%

“…As a family of transcription factors, cytokines, phosphatases, and other enzymes, IEGs are important determinants of delayed gene expression and phenotypic outcomes (17,18). We previously reported that simultaneous exposure of EC to EGF and thrombin caused a synergistic induction of the IEG mitogen-activated protein kinase phosphatase-1 (MKP-1) and enhanced migration of EC in vitro (7). EGF is a well known stimulator of cell growth and induces EC proliferation, migration, and angiogenesis (19).…”

mentioning

confidence: 99%

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STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

Waitkus

Chandrasekharan

Willard

et al. 2013

Journal of Biological Chemistry

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Section: Inhibition Of Akt Is Required For Stat3 Ser 727 Phosphorylatsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 69%

mentioning

confidence: 99%

mentioning

confidence: 99%

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STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

Waitkus

Chandrasekharan

Willard

et al. 2013

Journal of Biological Chemistry

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“…Of note, PAR2-mediated EGFR transactivation in HaCaT keratinocytes induces ERK signaling and leads to secretion of transforming growth factor-beta-1 (TGF-β1 ). Furthermore, a recent study has shown that synergistic signaling involving PAR1 and ErbB2/ HER2/EGFR2 enhances induction of the atherosclerosis-associated protein MAPK phosphatase-1 in an ERK1/2 independent, JNK and VEGFR-2 dependent process (Chandrasekharan et al, 2010).…”

Section: Signal Tranductionmentioning

confidence: 99%

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

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About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

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Proteinase-activated receptor 1- and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation

Mussbach

Henklein

Westermann

et al. 2014

J Cancer Res Clin Oncol

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Synergistic Induction of Mitogen-Activated Protein Kinase Phosphatase-1 by Thrombin and Epidermal Growth Factor Requires Vascular Endothelial Growth Factor Receptor-2

Abstract: Objective-To determine the molecular mechanism underlying the synergistic response of mitogen-activated protein kinase phosphatase-1 (MKP-1), which is induced by thrombin and epidermal growth factor (EGF). Methods and Results

Cited by 14 publications

References 29 publications

STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Proteinase-activated receptor 1- and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation

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