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Thrombin
F the upstream p42/44 MAPK cascade component RAF by PKG [37].Thrombin, VEGF and Histamine mediated MLC activationThrombin regulates endothelial permeability, inflammation and other events via activation of thrombin receptors such as PAR-1 by proteolytically cleaving the Nterminus of these receptors [24]. PAR-1 is the main receptor in the regulation of endothelial permeability (Additional File 1, Figure S1). It interacts with Gq to increase the concentration of Ca2+ and activate protein kinase C, inositol 1, 4, 5-triphosphate and diacylglycerol [25]. It is also linked to G12/13 [26] to activate the small G-protein Rho [27].VEGF mediated ERK activationVEGF regulates angiogenesis, cancer and microvascular permeability under various physiological and pathological conditions by activating transmembrane tyrosine kinase receptors VEGFR-2 and Flt-1, which promotes mitogenic, chemotactic, and prosurvival signalling and activates phospholipase C (PLC), intracellular Ca2+, and various protein kinase C (PKC) isoforms. In particular, VEGF activates ERK-1/2 via the Raf-MEK-ERK cascadeMLC of myosin II plays a critical role in controlling actomyosin contractility in both smooth muscle and nonmuscle cells [38-40]. MLC phosphorylation is regulated by the balance of two enzymatic activities, i.e., MLCK and myosin phosphatase (MYCP). MLCK is regulated by Ca 2+ /calmodulin and is believed to be a major kinase in both smooth muscle and nonmuscle PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/13485127 cells. In addition, Rho-kinase (ROCK) can directly phosphorylate MLC in vitro [41]. MYCP is a holoenzyme composed of three subunits: a catalytic subunit of 38 kDa that was identified as protein phosphatase 1 (PP1) catalytic subunit -isoform (PP1C) [42] and two noncatalytic subunits of 21 and 110-130 kDa [43,44]. The larger one, called myosin phosphatase targeting subunit 1 (MYPT1), binds to the catalytic subunit and targets it 6-(Thiophen-3-yl)pyridin-3-amine to MLC, providing substrate specificity [45]. ROCK and PKC have been proposed to mediate the inhibition of smooth muscle MYCP, leading to increased MLC phosphorylation in response to various agonists.Wei et al. BMC Systems Biology 2011, 5:112 http://www.biomedcentral.com/1752-0509/5/Page 4 ofPhosphorylation of the MYPT1 regulatory site (Thr695 in chicken MYPT1) by ROCK induces inhibition of MYCP activity [46]. Some experimental findings suggest that CPI-17, a soluble globular protein, is involved in PKC-dependent inhibition of MYCP and it has thus been considered as a specific inhibitor for MYCP [47]. Detail description of signaling cascades used in this model was provided the Additional File 3.Results and DiscussionModel validation with experimental studies of the regulation of MLC activation, calcium release, and Rho activation by thrombinOur simulation model was first validated by determining whether the simulation results were consistent with experimental observations of MLC activation and calcium release by the single mediator thrombin. Thrombin-mediated processes were investigated computationally by zeroing out the initial concentration of VEGF and histamine. It has PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/8086425 been observed that MLC activation increases from low initial levels to 39 ?2 , 66 tert-Butyl 2,2-difluoro-3-(methacryloyloxy)pentanoate ?10, 68 ?13 , 64 ?13 , and 67 ?9 of the MLC population at 30s, 60s, 2.5 min, 15 min, and 30 min after thrombin stimulation, respectively, which subsequently drops to 48 at 60 min [48]. The amplitude of MLC activation has been found to correlate linearly with the strength of endothelial cell contraction [49,50]. As illustrated in Figure 2 (L.