scholarly journals A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast

2004 ◽  
Vol 166 (2) ◽  
pp. 205-211 ◽  
Author(s):  
Prasenjit Mitra ◽  
Yingjie Zhang ◽  
Lucia E. Rameh ◽  
Maria P. Ivshina ◽  
Dannel McCollum ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Mammalian Cells ◽  
Class I ◽  
Unexpected Finding ◽  
Class Iii ◽  
Growth And Survival ◽  
Higher Eukaryotes ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatidylinositol 4 ◽  
Phosphatase And Tensin Homologue

The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases.

Abstract 17105: Is There a Difference in Lean and Fat Mass in HF Patients Based on NYHA Classifications (I-II versus III-IV)?

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Christine Haedtke ◽  
Debra K Moser ◽  
Susan J Pressler ◽  
Terry Lennie
Keyword(s):  
Body Composition ◽  
Fat Mass ◽  
Lean Mass ◽  
Nyha Class ◽  
Class I ◽  
Unexpected Finding ◽  
Class Iii ◽  
Medication Regimen ◽  
Cross Sectional ◽  
Nyha Classification

Introduction: As NYHA Class increases from I (ordinary physical activity does not cause undue fatigue), to Class IV (Symptoms are present while at rest) physical limitations become severe. It has previously been shown that HF patients have increased fat within the muscle thus decreasing exercise performance and tolerance. It is unclear if all NYHA classes are similarly affected. Hypothesis: HF patients with NYHA class III-IV will have more fat and less lean mass than those with NYHA class I-II. Methods: Secondary data analysis using cross sectional data from N=253. The parent study was a multicenter study about nutrition and body composition among patients with HF (preserved or reduced, and NYHA classification I-IV) who had been on a stable medication regimen, able to participate in dual-energy X-ray absorptiometry scan and/or BodPod body composition measures, able to read and speak English, and had no cognitive impairment. Women and men were analyzed separately due to known differences in fat and lean mass. Results: Table 1: Sample characteristic’s Testing the hypothesis using 2-way ANOVA and comparing the percentage of body weight that is lean and fat mass in NYHA class I-II vs III-IV found the interaction of gender and NYHA was not significant in either % lean or %fat (p=0.221, 0.190 respectively). NYHA class by itself was not significant (p=0.067) in %lean but was significant in %fat (p=0.046). Gender was significant in both %lean and %fat with men having 9.6% less fat (1.139 SE) and 9.8% more lean mass (1.066 SE) (p≤0.001). NYHA class III-IV had 2.3% (1.139 SE) more fat than those in NYHA class I-II. The R squared was 0.265 and adjusted R squared was 0.256. Conclusions: Part of our hypothesis was correct in that NYHA class III-IV had more fat mass than those in class I-II, but no difference was found in lean. This is an unexpected finding as healthy people gain fat mass while losing lean mass as they age. Additional studies are needed to further examine this result.

scholarly journals Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3931 ◽  
Author(s):  
Fatemeh Mazloumi Gavgani ◽  
Victoria Smith Arnesen ◽  
Rhîan Jacobsen ◽  
Camilla Krakstad ◽  
Erling Hoivik ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Gene Copy Number ◽  
Biochemical Properties ◽  
Class I ◽  
Gene Copy ◽  
Gene Encoding ◽  
Cellular Processes ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.

Regulation of class III (Vps34) PI3Ks

2007 ◽  
Vol 35 (2) ◽  
pp. 239-241 ◽  
Author(s):  
Y. Yan ◽  
J.M. Backer
Keyword(s):  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Class Iii ◽  
Lipid Kinase ◽  
Intracellular Targeting ◽  
Lipid Product ◽  
Important Regulator ◽  
Phosphoinositide 3 Kinase ◽  
Vacuolar Protein

The class III PI3K (phosphoinositide 3-kinase), Vps34 (vacuolar protein sorting 34), was first identified as a regulator of vacuolar hydrolase sorting in yeast. Unlike other PI3Ks, the Vps34 lipid kinase specifically utilizes phosphatidylinositol as a substrate, producing the single lipid product PtdIns3P. While Vps34 has been studied for some time in the context of endocytosis and vesicular trafficking, it has more recently been implicated as an important regulator of autophagy, trimeric G-protein signalling, and the mTOR (mammalian target of rapamycin) nutrient-sensing pathway. The present paper will focus on studies that describe the regulation of hVps34 (human Vps34) intracellular targeting and enzymatic activity in yeast and mammalian cells.

scholarly journals hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells

2009 ◽  
Vol 417 (3) ◽  
pp. 747-755 ◽  
Author(s):  
Ying Yan ◽  
Rory J. Flinn ◽  
Haiyan Wu ◽  
Rachel S. Schnur ◽  
Jonathan M. Backer
Keyword(s):  
Mammalian Cells ◽  
Specific Activity ◽  
Gene Activation ◽  
Nutrient Sensing ◽  
Beclin 1 ◽  
Class Iii ◽  
Acetoxymethyl Ester ◽  
Phosphoinositide 3 Kinase ◽  
Vacuolar Protein

The mammalian Class III PI3K (phosphoinositide 3-kinase), hVps34 [mammalian Vps (vacuolar protein sorting) 34 homologue], is an important regulator of vesicular trafficking, autophagy and nutrient sensing. In yeast, Vps34 is associated with a putative serine/threonine protein kinase, Vps15, which is required for Vps34p activity. The mammalian homologue of Vps15p, hVps15 (formerly called p150), also binds to hVps34, but its role in hVps34 signalling has not been evaluated. In the present study we have therefore compared the activity and regulation of hVps34 expressed without or with hVps15. We find that hVps34 has low specific activity when expressed alone; co-expression with hVps15 leads to a marked increase in activity. Notably, beclin-1/UVRAG (UV radiation resistance-associated gene) activation of hVps34 requires co-expression with hVps15; this may be explained by the observation that beclin-1/UVRAG expression increases hVps34/hVps15 binding. Regulation of hVps34 activity by nutrients also requires co-expression with hVps15. Finally, given a recent report that hVps34 activity requires Ca2+/CaM (calmodulin), we considered whether hVps15 might be involved in this regulation. Although hVps34 does bind CaM, we find its activity is not affected by treatment of cells with BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid tetrakis(acetoxymethyl ester)] or W7. Removal of CaM by EDTA or EGTA washes has no effect on hVps34 activity, and hVps34 activity in vitro is unaffected by Ca2+ chelation. The results of the present study show that, in mammalian cells, hVps34 activity is regulated through its interactions with hVps15, but is independent of Ca2+/CaM.

scholarly journals Modulation of the fate of cytoplasmic mRNA by AU-rich elements: key sequence features controlling mRNA deadenylation and decay.

1997 ◽  
Vol 17 (8) ◽  
pp. 4611-4621 ◽  
Author(s):  
N Xu ◽  
C Y Chen ◽  
A B Shyu
Keyword(s):  
Mammalian Cells ◽  
Class Ii ◽  
Class I ◽  
Untranslated Regions ◽  
Sequence Motif ◽  
Class Iii ◽  
Decay Kinetics ◽  
Close Proximity

Regulation of cytoplasmic deadenylation has a direct impact on the fate of mRNA and, consequently, its expression in the cytoplasm. AU-rich elements (AREs) found in the 3' untranslated regions of many labile mRNAs are the most common RNA-destabilizing elements known in mammalian cells. AREs direct accelerated deadenylation as the first step in mRNA turnover. Recently we have proposed that AREs can be divided into three different classes. mRNAs bearing either the class I AUUUA-containing ARE or the class III non-AUUUA ARE display synchronous poly(A) shortening, whereas class II ARE-containing mRNAs are deadenylated asynchronously, with the formation of poly(A)- intermediates. In this study, we have systematically characterized the deadenylation kinetics displayed by various AREs and their mutant derivatives. We find that a cluster of five or six copies of AUUUA motifs in close proximity forming various degrees of reiteration is the key feature that dictates the choice between processive versus distributive deadenylation. An AU-rich region 20 to 30 nucleotides long immediately 5' to this cluster of AUUUA motifs can greatly enhance the destabilizing ability of the AUUUA cluster and is, therefore, an integral part of the class I and class II AREs. These two features are the defining characteristics of class II AREs. Our results are consistent with the interpretation that the pentanucleotide AUUUA, rather than the nonamer UUAUUUA(U/A)(U/A), is both an essential and the minimal sequence motif of AREs. Our study provides the groundwork for future characterization of ARE-binding proteins identified by in vitro gel shift assays in order to stringently define their potential role in the ARE-mediated decay pathway. Moreover, transformation of deadenylation kinetics from one type to the other by mutations of AREs implies the existence of cross talk between the ARE and 3' poly(A) tail, which dictates the decay kinetics.

scholarly journals Class III phosphoinositide 3-kinase–Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes

2003 ◽  
Vol 376 (3) ◽  
pp. 577-586 ◽  
Author(s):  
Amina TASSA ◽  
Marie Paule ROUX ◽  
Didier ATTAIX ◽  
Daniel M. BECHET
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Amino Acid Starvation ◽  
Class I ◽  
C2c12 Myotubes ◽  
Dependent Manner ◽  
Class Iii ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Increased proteolysis contributes to muscle atrophy that prevails in many diseases. Elucidating the signalling pathways responsible for this activation is of obvious clinical importance. Autophagy is a ubiquitous degradation process, induced by amino acid starvation, that delivers cytoplasmic components to lysosomes. Starvation markedly stimulates autophagy in myotubes, and the present studies investigate the mechanisms of this regulation. In C2C12 myotubes incubated with serum growth factors, amino acid starvation stimulated autophagic proteolysis independently of p38 and p42/p44 mitogen-activated protein kinases, but in a PI3K (phosphoinositide 3-kinase)-dependent manner. Starvation, however, did not alter activities of class I and class II PI3Ks, and was not sufficient to affect major signalling proteins downstream from class I PI3K (glycogen synthase kinase, Akt/protein kinase B and protein S6). In contrast, starvation increased class III PI3K activity in whole-myotube extracts. In fact, this increase was most pronounced for a population of class III PI3K that coimmunoprecipitated with Beclin1/Apg6 protein, a major determinant in the initiation of autophagy. Stimulation of proteolysis was reproduced by feeding myotubes with synthetic dipalmitoyl-PtdIns3P, the class III PI3K product. Conversely, protein transfection of anti-class III PI3K inhibitory antibody into starved myotubes inverted the induction of proteolysis. Therefore, independently of class I PI3K/Akt, protein S6 and mitogen-activated protein kinase pathways, amino acid starvation stimulates proteolysis in myotubes by regulating class III PI3K–Beclin1 autophagic complexes.

Controlling cell growth and survival through regulated nutrient transporter expression

2007 ◽  
Vol 406 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Aimee L. Edinger
Keyword(s):  
Cell Growth ◽  
Mammalian Cells ◽  
Growth Control ◽  
Cellular Growth ◽  
Growth And Survival ◽  
Tumour Suppression ◽  
Nutrient Transporter ◽  
Phosphoinositide 3 Kinase ◽  
Cell Growth And Proliferation ◽  
Transporter Expression

Although all cells depend upon nutrients they acquire from the extracellular space, surprisingly little is known about how nutrient uptake is regulated in mammalian cells. Most nutrients are brought into cells by means of specific transporter proteins. In yeast, the expression and trafficking of a wide variety of nutrient transporters is controlled by the TOR (target of rapamycin) kinase. Consistent with this, recent studies in mammalian cells have shown that mTOR (mammalian TOR) and the related protein, PI3K (phosphoinositide 3-kinase), play central roles in coupling nutrient transporter expression to the availability of extrinsic trophic and survival signals. In the case of lymphocytes, it has been particularly well established that these extrinsic signals stimulate cell growth and proliferation in part by regulating nutrient transporter expression. The ability of growth factors to control nutrient access may also play an important role in tumour suppression: the non-homoeostatic growth of tumour cells requires that nutrient transporter expression is uncoupled from trophic factor availability. Also supporting a link between nutrient transporter expression levels and oncogenesis, several recent studies demonstrate that nutrient transporter expression drives, rather than simply parallels, cellular metabolism. This review summarizes the evidence that regulated nutrient transporter expression plays a central role in cellular growth control and highlights the implications of these findings for human disease.

scholarly journals Phosphatidylinositol kinases (version 2020.2) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (2) ◽  
Author(s):  
Mohib Uddin
Keyword(s):  
Molecular Weight ◽  
Calcium Binding ◽  
Class Ii ◽  
Catalytic Subunit ◽  
Class I ◽  
Regulatory Subunit ◽  
Class Iii ◽  
Regulatory Subunits ◽  
Phosphatidylinositol 4 ◽  
Class Ib

Phosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.Phosphatidylinositol 3-kinasesPhosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP2). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. wortmannin and LY 294002 are widely-used inhibitors of PI3K activities. wortmannin is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110β and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2α, β and β, and include Ras-binding, Phox homology and two C2domains.The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).Phosphatidylinositol 4-kinasesPhosphatidylinositol 4-kinases (EC 2.7.1.67) generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.

The regulation and function of Class III PI3Ks: novel roles for Vps34

2008 ◽  
Vol 410 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Jonathan M. Backer
Keyword(s):  
Protein Synthesis ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Class Iii ◽  
Endocytic Sorting ◽  
Vacuolar Sorting ◽  
Phosphoinositide 3 Kinase ◽  
Sorting System ◽  
Vacuolar Protein ◽  
And Function

The Class III PI3K (phosphoinositide 3-kinase), Vps34 (vacuolar protein sorting 34), was first described as a component of the vacuolar sorting system in Saccharomyces cerevisiae and is the sole PI3K in yeast. The homologue in mammalian cells, hVps34, has been studied extensively in the context of endocytic sorting. However, hVps34 also plays an important role in the ability of cells to respond to changes in nutrient conditions. Recent studies have shown that mammalian hVps34 is required for the activation of the mTOR (mammalian target of rapamycin)/S6K1 (S6 kinase 1) pathway, which regulates protein synthesis in response to nutrient availability. In both yeast and mammalian cells, Class III PI3Ks are also required for the induction of autophagy during nutrient deprivation. Finally, mammalian hVps34 is itself regulated by nutrients. Thus Class III PI3Ks are implicated in the regulation of both autophagy and, through the mTOR pathway, protein synthesis, and thus contribute to the integration of cellular responses to changing nutritional status.

scholarly journals Phosphatidylinositol kinases in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Mohib Uddin
Keyword(s):  
Molecular Weight ◽  
Calcium Binding ◽  
Class Ii ◽  
Catalytic Subunit ◽  
Class I ◽  
Regulatory Subunit ◽  
Class Iii ◽  
Regulatory Subunits ◽  
Phosphatidylinositol 4 ◽  
Class Ib

Phosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.Phosphatidylinositol 3-kinasesPhosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP2). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. wortmannin and LY 294002 are widely-used inhibitors of PI3K activities. wortmannin is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110β and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2α, β and β, and include Ras-binding, Phox homology and two C2 domains.The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).Phosphatidylinositol 4-kinasesPhosphatidylinositol 4-kinases (EC 2.7.1.67) generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.

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