1,721,035 research outputs found
Rethinking phosphatidylinositol 3-monophosphate
No full textAbstractA generally accepted view considers phosphatidylinositol 3-monophosphate (PtdIns3P) as a lipid confined to the endosomal compartment where it regulates trafficking pathways and is produced constitutively and exclusively by class III phosphoinositide 3-kinase (PI3K). Recent evidence suggests that this phosphoinositide has a more complex role as a second messenger involved in different physiological and pathological events and that specific intracellular localization of kinases and/or phosphatases is critical for PtdIns3P synthesis and PtdIns3P-dependent intracellular functions. Here, we review the current knowledge of the regulation and function of PtdIns3P and discuss how the view of PtdIns3P changed in the last few years
New insight into the intracellular roles of class II phosphoinositide 3-kinases
No full textIn the last few years, an increased attention to class II isoforms of phosphoinositide 3-kinase (PI3K) has emerged, mainly fuelled by evidence suggesting a distinct non-redundant role for these enzymes compared with other PI3Ks. Despite this renewed interest, many questions remain on the specific functions regulated by these isoforms and their mechanism of activation and action. In the present review, we discuss results from recent studies that have provided some answers to these questions
Regulation and cellular functions of class II phosphoinositide 3-kinases
No full textClass II isoforms of PI3K (phosphoinositide 3-kinase) are still the least investigated and characterized of all PI3Ks. In the last few years, an increased interest in these enzymes has improved our understanding of their cellular functions. However, several questions still remain unanswered on their mechanisms of activation, their specific downstream effectors and their contribution to physiological processes and pathological conditions. Emerging evidence suggests that distinct PI3Ks activate different signalling pathways, indicating that their functional roles are probably not redundant. In the present review, we discuss the recent advances in our understanding of mammalian class II PI3Ks and the evidence suggesting their involvement in human diseases. © The Authors Journal compilation © 2012 Biochemical Society
Emerging roles of phosphatidylinositol 3-monophosphate as a dynamic lipid second messenger
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Phosphoinositide 3-kinase-dependent regulation of phospholipase Cγ
No full textActivation of the enzyme PLC (phospholipase C) leads to the formation of second messengers Ins(1,4,5)P3 and diacylglycerol. RTKs (receptor tyrosine kinases) activate this reaction through PLCγ isoenzymes. It has been shown that PI3K (phosphoinositide 3-kinase) may regulate PLCγ activity through the interaction of PI3K product PtdIns(3,4,5)P3 and the PLCγ PH domain (pleckstrin homology domain). Here, we analyse the potential functional roles of the PI3K/PLC pathway. ©2007 Biochemical Society
Targeting p110gamma in gastrointestinal cancers: attack on multiple fronts
Full text linkPhosphoinositide 3-kinases (PI3Ks) regulate several cellular functions that are critical for cancer progression and development, including cell survival, proliferation and migration. Three classes of PI3Ks exist with the class I PI3K encompassing four isoforms of the catalytic subunit known as p110α, p110β, p110γ and p110δ. Although for many years attention has been mainly focused on p110α recent evidence supports the conclusion that p110β, p110γ and p110δ can also have a role in cancer. Amongst these, accumulating evidence now supports the conclusion that p110γ is involved in several cellular processes associated with cancer development and progression and indeed this specific isoform has emerged as a novel important player in cancer progression. Studies from our laboratory have identified a specific overexpression of p110γ in human pancreatic ductal adenocarcinoma (PDAC) and in hepatocellular carcinoma (HCC) tissues compared to their normal counterparts. Our data have further established that selective inhibition of this PI3K isoform is able to block PDAC and HCC cell proliferation, strongly suggesting that pharmacological inhibition of this enzyme can directly affect these tumors growth. Furthermore increasing evidence suggests that p110γ plays also a key role in the interactions between cancer cells and tumor microenvironment and in particular in tumor-associated immune response. It has also been reported that p110γ can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110γ has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110γ plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110γ in gastrointestinal tumor development and progression and how targeting this enzyme might represent a way to target very aggressive tumors such as pancreatic and liver cancer on multiple fronts
Signalling Properties of Inositol Polyphosphates
Full text linkSeveral studies have identified specific signalling functions for inositol polyphosphates
(IPs) in different cell types and have led to the accumulation of new information regarding their
cellular roles as well as new insights into their cellular production. These studies have revealed
that interaction of IPs with several proteins is critical for stabilization of protein complexes and for
modulation of enzymatic activity. This has not only revealed their importance in regulation of several
cellular processes but it has also highlighted the possibility of new pharmacological interventions in
multiple diseases, including cancer. In this review, we describe some of the intracellular roles of IPs
and we discuss the pharmacological opportunities that modulation of IPs levels can provide
Analysis, regulation, and roles of endosomal phosphoinositides
No full textPhosphoinositides (PIs) are minor lipid components of cellular membranes that play critical roles in membrane dynamics, trafficking, and cellular signaling. Among the seven naturally occurring PIs, the monophosphate phosphatidylinositol 3-phosphate (PtdIns3P) and the bisphosphate phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] have been mainly associated with endosomes and endosomal functions. Metabolic labeling and HPLC analysis revealed that a bulk of PtdIns3P is constitutively present in cells, making it the only detectable product of the enzymes phosphoinositide 3-kinases in unstimulated, normal cells. The use of specific tagged-PtdIns3P-binding domains later demonstrated that this constitutive PtdIns3P accumulates in endosomes where it critically regulates trafficking and membrane dynamics
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