• Biomolecules & Therapeutics
• /
• v.25 no.1
• /
• pp.12-25
• /
• 2017

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas ${\beta}$-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of ${\beta}$-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of ${\beta}$-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or ${\beta}$-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or ${\beta}$-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

• Korean Journal of Pharmacognosy
• /
• v.34 no.1 s.132
• /
• pp.91-99
• /
• 2003

Ras proteins play an important role in intracellular signal transduction pathways involved in cell growth and the mutated twas genes have been found in thirty percent of human cancers. Ras proteins (H-, K- and N-Ras) are small guanine nucleotide binding proteins that undergo a series of posttranslational modifications including the farnesylation onto cysteine 186 at C-terminal of Ras by farnesyl protein transferase (FPTase). This is a mandatory process for retention of transforming ability. Therefore, inhibitors of FPTase have a promising to be effective antitumor agents. In our screening program for FPTase inhibitors, the methanol extracts of 193 plants were screened for the inhibitory activity against FPTase partially purified from the rat brain. Extracts of 7species plants including Areca catechu, Saururus chinensis, Curcuma longa, Artemisa princeps, Paeonia suffruticosa, Spatholobus suberectus, Cinnamomum cassia, Cinnamomum japonicum inhibited more than 60% of FPTase activity at a concentration of $100\;{\mu}g/ml$.

• Toxicological Research
• /
• v.31 no.4
• /
• pp.339-345
• /
• 2015

CYP1A1 is a phase I xenobiotic-metabolizing enzyme whose expression is mainly driven by AhR. Endosulfan is an organochlorine pesticide used agriculturally for a wide range of crops. In this study, we investigated the effect of endosulfan on CYP1A1 expression and regulation. Endosulfan significantly increased CYP1A1 enzyme activity as well as mRNA and protein levels. In addition, endosulfan markedly induced XRE transcriptional activity. CH-223191, an AhR antagonist, blocked the endosulfan-induced increase in CYP1A1 mRNA and protein expression. Moreover, endosulfan did not induce CYP1A1 gene expression in AhR-deficient mutant cells. Furthermore, endosulfan enhanced the phosphorylation of calcium calmodulin (CaM)-dependent protein kinase (CaMK) and protein kinase C (PKC). In conclusion, endosulfan-induced up-regulation of CYP1A1 is associated with AhR activation, which may be mediated by PKC-dependent pathways.

• Smart Structures and Systems
• /
• v.8 no.1
• /
• pp.39-52
• /
• 2011

We are developing a biomimetic robot based on the Sea Lamprey. The robot consists of a cylindrical electronics bay propelled by an undulatory body axis. Shape memory alloy (SMA) actuators generate propagating flexion waves in five undulatory segments of a polyurethane strip. The behavior of the robot is controlled by an electronic nervous system (ENS) composed of networks of discrete-time map-based neurons and synapses that execute on a digital signal processing chip. Motor neuron action potentials gate power transistors that apply current to the SMA actuators. The ENS consists of a set of segmental central pattern generators (CPGs), modulated by layered command and coordinating neuron networks, that integrate input from exteroceptive sensors including a compass, accelerometers, inclinometers and a short baseline sonar array (SBA). The CPGs instantiate the 3-element hemi-segmental network model established from physiological studies. Anterior and posterior propagating pathways between CPGs mediate intersegmental coordination to generate flexion waves for forward and backward swimming. The command network mediates layered exteroceptive reflexes for homing, primary orientation, and impediment compensation. The SBA allows homing on a sonar beacon by indicating deviations in azimuth and inclination. Inclinometers actuate a bending segment between the hull and undulator to allow climb and dive. Accelerometers can distinguish collisions from impediment to allow compensatory reflexes. Modulatory commands mediate speed control and turning. A SBA communications interface is being developed to allow supervised reactive autonomy.

• The Korean Journal of Physiology and Pharmacology
• /
• v.4 no.5
• /
• pp.339-346
• /
• 2000

Using murine immortalized microglial cells (BV-2), we examined the regulation of RANTES production stimulated by lipopolysaccharide (LPS), focusing on the role of mitogen-activated protein kinase (MAPK) and nuclear factor $(NF)-{\kappa}B.$ The result showed that RANTES (regulated upon activation of normal T cell expressed and secreted) was induced at the mRNA and protein levels in a dose- and time-dependent manner in response to LPS. From investigations of second messenger pathways involved in regulating the secretion of RANTES, we found that LPS induced phosphorylation of extracellular signal-regulated kinase (Erk), p38 MAPK and c-Jun-N-terminal kinase (JNK), and activated $(NF)-{\kappa}B.$ To determine whether this MAPK phosphorylation is involved in LPS-stimulated RANTES production, we used specific inhibitors for p38 MAPK and Erk, SB 203580 and PD 98059, respectively. LPS-induced RANTES production was reduced approximately 80% at $25\;{\mu}M$ of SB 203580 treatment. But PD 98059 did not affect RANTES production. Pyrrolidine-dithiocarbamate (PDTC), $(NF)-{\kappa}B$ inhibitor, reduced RANTES secretion. These results suggest that LPS-induced RANTES production in microglial cells (BV-2) is mainly mediated by the coordination of p38 MAPK and $(NF)-{\kappa}B$ cascade.

• The Korean Journal of Physiology and Pharmacology
• /
• v.18 no.1
• /
• pp.73-78
• /
• 2014

Cell death and survival are tightly controlled through the highly coordinated activation/inhibition of diverse signal transduction pathways to insure normal development and physiology. Imbalance between cell death and survival often leads to autoimmune diseases and cancer. Death receptors sense extracellular signals to induce caspase-mediated apoptosis. Acting upstream of CED-3 family proteases, such as caspase-3, Bcl-2 prevents apoptosis. Using short hairpin RNAs (shRNAs), we suppressed Bcl-2 expression in Jurkat T cells, and this increased TCR-triggered AICD and enhanced TNFR gene expression. Also, knockdown of Bcl-2 in Jurkat T cells suppressed the gene expression of FLIP, TNF receptor-associated factors 3 (TRAF3) and TRAF4. Furthermore, suppressed Bcl-2 expression increased caspase-3 and diminished nuclear factor kappa B (NF-${\kappa}B$) translocation.

• The Korean Journal of Physiology and Pharmacology
• /
• v.13 no.6
• /
• pp.483-489
• /
• 2009

Despite the potential importance of the human regulator of calcineurin 1 (RCAN-1) gene in the modulation of cell survival under stress, little is known about its role in death-inducing signal pathways. In this study, we addressed the effects of RCAN1.4 knockdown on cellular susceptibility to apoptosis and the activation of death pathway proteins. Transfection of siRNAs against RCAN1.4 resulted in enhanced Fas- and etoposide-induced apoptosis, which was associated with increased expression and translocation of Bax to mitochondria. Our results suggest that enhanced expression and activation of p53 was responsible for the upregulation of Bax and the increased sensitivity to apoptosis, which could be reversed by p53 knockdown. To explain the observed upregulation of p53, we propose a downregulation of the ubiquitin ligase HDM2, probably translationally. These findings show the importance of appropriate RCAN1.4 expression in the modulation of cell survival and reveal a link between RCAN1.4 and p53.

• Macromolecular Research
• /
• v.15 no.4
• /
• pp.370-378
• /
• 2007

Mechanical stimulation is known to activate several cellular signal transduction pathways, leading to the induction of signaling molecules and extracellular matrix (ECM) proteins, thereby modulating cellular activities, such as proliferation and survival. In this study, primary human dermal fibroblasts (HDFs) were seeded onto chitosan-based scaffolds, and then cultured for 3 weeks in a bioreactor under a cyclic strain of 1 Hz frequency. Compared to control samples cultured under static conditions, the application of a cyclic strain stimulated the proliferation of HDFs in I week, and by week 3 the thickness of the cell/scaffold composites increased 1.56 fold. Moreover, immunohistochemical staining of the culture media obtained from the cell/scaffold samples subjected to the cyclic strain, revealed increases in the expression and secretion of ECM proteins, such as fibronectin and collagen. These results suggest that the preconditioning of cell/scaffold composites with a cyclic strain may enhance the proliferation of HDFs, and even facilitate integration of the engineered artificial dermal tissue into the host graft site.

• Interdisciplinary Bio Central
• /
• v.4 no.2
• /
• pp.3.1-3.7
• /
• 2012

Epidermal growth factor receptor (EGFR) is a member of the ErbB family (ErbB1-4) of receptor tyrosine kinases (RTKs). EGFR controls numerous physiological functions, including cell proliferation, migration, differentiation and survival. Importantly, aberrant signaling by EGFR has been linked to human cancers in which EGFR and its various ligands are frequently overexpressed or mutated. EGFR coordinates activation of multiple downstream factors and is subject of various regulatory processes as it mediates biology of the cell it resides in. Therefore, many studies have been devoted to understanding EGFR biology and targeting the protein for the goal of controlling tumor in clinical settings. Endocytic regulation of EGFR offers a promising area for targeting EGFR activity. Upon ligand binding, the activated receptor undergoes endocytosis and becomes degraded in lysosome, thereby terminating the signal. En route to lysosome, the receptor becomes engaged in activating various signaling pathways including PI-3K, MAPK and Src, and endocytosis may offer both spatial and temporal regulation of downstream target activation. Therefore, endocytosis is an important regulator of EGFR signaling, and increasing emphasis is being placed on endocytosis in terms of cancer treatment and understanding of the disease. In this review, EGFR signaling pathway and its intricate regulation by endocytosis will be discussed.

• Biomolecules & Therapeutics
• /
• v.24 no.6
• /
• pp.589-594
• /
• 2016

Insulin is a peptide hormone of the endocrine pancreas and exerts a wide variety of physiological actions in insulin sensitive tissues, such as regulation of glucose homeostasis, cell growth, differentiation, learning and memory. However, the role of insulin in osteoblast cells remains to be fully characterized. In this study, we demonstrated that the insulin (100 nM) has the ability to stimulate the phosphorylation of protein kinase B (Akt/PKB) and extracellular signal-regulated kinase (ERK) and the levels of inhibin-${\beta}E$ in the osteoblast-like UMR-106 cells. This insulin-stimulated activities were abolished by the PI3K and MEK1 inhibitors LY294002 and PD98059, respectively. This is the first report proving that insulin is a potential candidate that enables the actions of inhibin-${\beta}E$ subunit of the TGF-${\beta}$ family. The current investigation provides a foundation for the realization of insulin as a potential stimulator in survival signaling pathways in osteoblast-like UMR-106 cells.