How phosphoinositide 3-phosphate controls growth downstream of amino acids and autophagy downstream of amino acid withdrawal

Ktistakis, Nicholas T.; Manifava, Maria; Schoenfelder, Priya; Rotondo, Sergio

doi:10.1042/bst20110684

Cited by 23 publications

(24 citation statements)

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“…27 To examine if basal autophagy in our cell line is also dependent on formation of PtdIns3P we used wortmannin, 28 a broad inhibitor of all PI 3-kinases which also inhibits PIK3C3 (also known as VPS34), the catalytic subunit of class III PtdIns 3-kinase responsible for the production of PtdIns3P, involved in autophagy. 29 In preliminary experiments we determined that simultaneous incubation of cells with wortmannin and the compounds that reveal basal autophagy gave inconsistent results. We decided therefore to pretreat cells with wortmannin for 15 min before addition of chloroquine, BafA1 or vinblastine.…”

Section: Bafa1 Reveals Basal Autophagy Without Further Complicating Amentioning

confidence: 99%

Characteristics and requirements of basal autophagy in HEK 293 cells

et al. 2013

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Basal autophagy-here defined as macroautophagic activity during cellular growth in normal medium containing amino acids and serum-appears to be highly active in many cell types and in animal tissues. here we characterized this pathway in mammalian heK 293 cells. First, we examined, side by side, three compounds that are widely used to reveal basal autophagy by blocking maturation of autophagosomes: bafilomycin a 1 (Bafa1), chloroquine and vinblastine. Only Bafa1 appeared to be without complicating side effects. chloroquine partially inhibited mechanistic target of rapamycin (MTOR) activity, which would induce autophagy induction as well as block autophagosome maturation. Vinblastine caused the distribution of early omegasome components into punctate phagophore assembly sites, and therefore it would also induce autophagy, complicating interpretation. Basal autophagy was significantly sensitive to inhibition by wortmannin, and therefore required formation of phosphatidylinositol 3-phosphate (Ptdins3P), but it was twice as resistant to wortmannin as starvation-induced autophagy. We also determined that basal autophagy was significantly suppressed by MTOR activation brought about by overexpression of RheB or activated RaGs. Finally we investigated the spatial relationship of nascent autophagosomes to the endoplasmic reticulum (eR) or to mitochondria by live imaging experiments under conditions that reveal basal autophagy (with Bafa1 treatment), or upon MTOR inactivation (which would result in autophagy induction). side-by-side comparison showed that under both basal and induced autophagy, 100% of autophagosomes first appeared in close proximity to eR strands. in parallel measurements, 40% were in close proximity to mitochondria under both conditions. We concluded that in heK 293 cells, basal autophagy is mechanistically similar to that induced by MTOR inactivation in all aspects examined.

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Section: Bafa1 Reveals Basal Autophagy Without Further Complicating Amentioning

confidence: 99%

Characteristics and requirements of basal autophagy in HEK 293 cells

et al. 2013

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“…In accordance with our results, insulin and amino acids were previously reported to induce endocytosis (Pitterle et al, 1999;Fagerholm et al, 2009) (Ktistakis et al, 2012). Thus, it is possible that in the presence of insulin and amino acids, annexin A5 downregulates copine 1 to maintain low levels of endocytosis.…”

Section: Discussionsupporting

confidence: 80%

“…Although amino acids are well-known inhibitors of autophagy, we observed an enhanced fluid phase endocytic uptake in the presence of amino acids (see Results, Chapter 4). In agreement with our findings, amino acids, in addition to inhibit the class III phosphatidylinositol 3-kinase complex I (PI 3 KI) that triggers autophagy, are thought to activate PI 3 K complex II (PI 3 KII), important for vesicle sorting during endocytosis and containing BIF-1, a curvature-sensing positive regulator (Ktistakis et al, 2012). Thus, it is possible that BAIAP2 association to lysosomal membranes in the presence of amino acids is related to the activation of the endocytosis in this condition.…”

Section: Identification Of Proteins With Altered Levels On Lysosomal supporting

confidence: 74%

“…Amino acids were also reported to positively regulate endocytosis. Their presence was shown to activate the Class III phosphatidylinositol 3-kinase complex II involved in endoytosis whereas their removal activates the Class III phosphatidylinositol 3-kinase complex I involved in autophagy (Ktistakis et al, 2012). Thus, it is conceivable that insulin and amino acids play opposite roles in autophagy and endocytosis.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Lysosomal Degradation by CA2+And CA2+-Binding Proteins

Cherfaoui¹

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“…However, with the recent development of class III-selective inhibitors, PtdIns(3) P has been demonstrated to regulate the activity of SGK3 in cells, opening up the possibility that co-inhibition of class I and III PI3Ks could be used to treat human PIK3CA-mutant cancers where SGK3 is amplifi ed and hyper-activated, such as in breast cancer ( 205 ). Furthermore class I and III PI3Ks regulate autophagy ( 206 ), a cellular process that in some situations helps drive tumor formation ( 207 ). Consequently the control of PtdIns(3)P levels in cancer cells could offer an additional therapeutic possibility.…”

Section: The Sac Phosphatases and Cancermentioning

confidence: 99%

Phosphatidylinositolphosphate phosphatase activities and cancer

Rudge

Wakelam

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org kinase pathways in regulating phosphoinositide signaling; however, all signaling pathways are subject to negative as well as positive control, pointing to a key role for inositol phospholipid phosphatases in cell and tissue regulation in health and disease. This review focuses upon this aspect of regulation, considering the importance of the many phosphatases that can act upon phosphoinositides, and we further consider the importance of each in malignancy. PHOSPHOINOSITIDE 3-KINASESIn mammals, the phosphoinositide 3-kinase (PI3K) isoforms responsible for phosphorylating the 3-hydroxyl group of the inositol headgroup of PtdIns, PtdIns(4)P, and PtdIns(4,5)P 2 have been divided into three classes: class I, class II, and class III.In response to activation of cell surface receptors, class I PI3Ks are responsible for phosphorylating PtdIns(4,5)P 2 to generate PtdIns(3,4,5)P 3 ( 3 ). There are four class I PI3Ks that exist as heterodimers of regulatory and catalytic subunits. The four distinct catalytic subunits, p110 ␣ , -␤ , -␥ , and -␦ , are further divided into class IA (p110 ␣ , -␤ , and -␦ ) and class IB (p110 ␥ ). Class IA PI3Ks bind the SH2 domain containing the p85 family of regulatory subunits (p85 ␣ , p85 ␤ , and p55) that bind to protein tyrosine phosphate residues in activated receptors, thus relieving p85-mediated Abstract Signaling through the phosphoinositide 3-kinase pathways mediates the actions of a plethora of hormones, growth factors, cytokines, and neurotransmitters upon their target cells following receptor occupation. Overactivation of these pathways has been implicated in a number of pathologies, in particular a range of malignancies. The tight regulation of signaling pathways necessitates the involvement of both stimulatory and terminating enzymes; inappropriate activation of a pathway can thus result from activation or inhibition of the two signaling arms . The focus of this review is to discuss, in detail, the activities of the identifi ed families of phosphoinositide phosphatase expressed in humans, and how they regulate the levels of phosphoinositides implicated in promoting malignancy. A series of tightly regulated lipid kinase and phosphatase enzyme activities coordinately convert phosphatidylinositol (PtdIns) into a network of phosphorylated derivatives, collectively called phosphoinositides. These differ in the number and position of the phosphate groups on the inositol head group: three PtdIns monophosphate isomers [PtdIns(3)P, PtdIns(4)P, and PtdIns(5)P], three PtdIns bisphosphate isomers [PtdIns(3,4)P 2 , PtdIns(3,5) P 2 , and PtdIns(4,5)P 2 ], and a single trisphosphate isomer [PtdIns(3,4,5)Phosphoinositide signaling is an extensively studied topic with clear evidence linking the pathway from the kinase to activation of AKT and TOR to a number of disease states. While these include malignancies, there is also strong evidence for other diseases, such as overgrowth syndromes. Most studies have focused upon the importance of the ...

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How phosphoinositide 3-phosphate controls growth downstream of amino acids and autophagy downstream of amino acid withdrawal

Cited by 23 publications

References 72 publications

Characteristics and requirements of basal autophagy in HEK 293 cells

Characteristics and requirements of basal autophagy in HEK 293 cells

Regulation of Lysosomal Degradation by CA2+And CA2+-Binding Proteins

Phosphatidylinositolphosphate phosphatase activities and cancer

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