2,710 research outputs found
LECTIN ACTIVATES PHOPSHOLIPASE C VIA TYROSINE PHOSPHORYLATION OF PLC-Υ1 IN A HUMAN T CELL
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Protein kinase C-alpha negatively regulates EGF-induced PLC-varepsilon activity through direct phosphorylation
No full text110sciescopu
Nudix-type motif 2 contributes to cancer proliferation through the regulation of Rag GTPase-mediated mammalian target of rapamycin complex 1 localization
No full textLysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2-silenced cells arrest in G0/G1 phases. Taken together, these results show that NUDT2 is a novel complex formation enhancing factor regulating mTORC1-Rag GTPase signaling that is crucial for cell growth control. ? 2017 Elsevier Inc.112sciescopu
Accumulating insights into the role of phospholipase D2 in human diseases
No full textPhospholipase D2 (PLD2) is a lipid-signaling enzyme that produces the signaling molecule phosphatidic acid (PA) by catalyzing the hydrolysis of phosphatidylcholine (PC). The molecular characteristics of PLD2, the mechanisms of regulation of its activity, its functions in the signaling pathway involving PA and binding partners, and its role in cellular physiology have been extensively studied over the past decades. Although several potential roles of PLD2 have been proposed based on the results of molecular and cell-based studies, the pathophysiological functions of PLD2 in vivo have not yet been fully investigated at the organismal level. Here, we address accumulated evidences that provide insight into the role of PLD2 in human disease. We summarize recent studies using animal models that provide direct evidence of the function of PLD2 in several pathological conditions such as vascular disease, immunological disease, and neurological disease. In light of the use of recently developed PLD2-specific inhibitors showing potential in alleviating pathological conditions, improving our understanding of the role of PLD2 in human disease would be necessary to target the regulation of PLD2 activity as a therapeutic strategy. © 2015close
Single particle tracking-based reaction progress kinetic analysis reveals a series of molecular mechanisms of cetuximab-induced EGFR processes in a single living cell
No full textCellular processes occur through the orchestration of multi-step molecular reactions. Reaction progress kinetic analysis (RPKA) can provide the mechanistic details to elucidate the multi-step molecular reactions. However, current tools have limited ability to simultaneously monitor dynamic variations in multiple complex states at the single molecule level to apply RPKA in living cells. In this research, a single particle tracking-based reaction progress kinetic analysis (sptRPKA) was developed to simultaneously determine the kinetics of multiple states of protein complexes in the membrane of a single living cell. The subpopulation ratios of different states were quantitatively (and statistically) reliably extracted from the diffusion coefficient distribution rapidly acquired by single particle tracking at constant and high density over a long period of time using super-resolution microscopy. Using sptRPKA, a series of molecular mechanisms of epidermal growth factor receptor (EGFR) cellular processing induced by cetuximab were investigated. By comprehensively measuring the rate constants and cooperativity of the molecular reactions involving four EGFR complex states, a previously unknown intermediate state was identified that represents the rate limiting step responsible for the selectivity of cetuximab-induced EGFR endocytosis to cancer cells. ? The Royal Society of Chemistry 2017.112Ysciescopu
On/Off-regulation of phospholipase C-gamma 1-mediated signal transduction
No full textAlterations in the production and regulation of lipid second messengers can give rise to key molecular lesions that trigger tumorigenesis and cancer progression. Especially, the hydrolysis of membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2), is mediated by a specific phospholipase C (PLC), which plays important roles in the regulation of various cell functions. PLC generates two intracellular messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which mediate the activation of protein kinase C (PKC) and intracellular Ca2+ release, respectively. Among the PLC isozymes, PLC-??1 contains two src homology (SH) 2 domains and one SH3 domain between the X and Y catalytic domains. The SH2 domains of PLC-??1 have been implicated in the association between PLC-??1 and activated receptor tyrosine kinases, and the SH3 domain of PLC-??1 has been reported to be responsible for the mitogenic effect of PLC-??1, suggesting that PLC-??1 exerts other actions that are independent of its lipase activity and appears to be involved in the SH domains. However, the physiological role of SH domains in the regulation of PLC-??1 is still unclear. We have recently characterized the regulation mechanism of PLC-??1 through protein-protein interactions. We have elucidated that PLC-??1 can serve as a guanine nucleotide exchange factor (GEF) for dynamin-1 through direct interaction via its SH3 domain. These results indicate that GEF function of PLC-??1 for dynamin-1 may link with PLC-??1's mitogenic actions. The SH3 domain of PLC-??1 can mediate Sos and PIKE activation by acting as GEF, suggesting that PLC-??1 plays an essential role on cellular proliferation through protein-protein interaction independent of its enzymatic activity. On the other hand, we have found that Cbl directly interacts with the SH3 domain of PLC-??1 and inhibits its tyrosine phosphorylation and enzymatic activity, suggesting that PLC-??1 can be off-regulated by protein-protein interaction. In addition, we demonstrate that Grb2 interacts with tyrosine phosphorylated PLC-??1 and acts as an inhibitor on PLC-??1-mediated signaling. These results suggest that Grb2, one of the key regulators of Ras/Raf/MAPK signaling pathway, may participate in the regulation of PLC-??1. Lastly, PLC-??1 forms a ternary complex with Jak2 and PTP-1B and negatively regulates GH-induced Jak2 phosphorylation. Taken together, our data strengthen the hypothesis that the interaction between PLC-??1 and effector proteins plays a key role in on- or off-regulating PLC-??1-mediated cellular proliferation independent its enzymatic activity. These results can provide novel insights to understand how PLC-??1 is regulated and involved in cellular growth and proliferation.close141
A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3 beta/JNK axis
No full textWe examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. During the pathological progress of acute liver injury, GSH levels are decreased, and this is significantly recovered upon the administration of CAY10594 at 6 hours post APAP challenge. GSK-3 beta (Serine 9)/JNK phosphorylation is mainly involved in APAPinduced liver injury. CAY10594 administration strongly blocked GSK-3 beta (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.11Ysciescopu
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