Regulation and cellular functions of class II phosphoinositide 3-kinases

Falasca, Marco; Maffucci, Tania

doi:10.1042/bj20120008

Cited by 139 publications

(178 citation statements)

References 98 publications

(246 reference statements)

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“…This is in accordance with previous fi ndings of intact insulin-stimulated PI3k activity in human skeletal muscle ( 12 ). Only a little is known about the function of class II PI3k, although it has been shown that the C2 ␤ subunit, which is encoded by the PIK3C2B gene, is directly activated by growth factors in vitro ( 45 ). It is therefore possible that the confi rmed by incubation of C2C12 cells in this study (32)(33)(34).…”

Section: Discussionsupporting

confidence: 78%

Gene expression in skeletal muscle after an acute intravenous GH bolus in human subjects: identification of a mechanism regulating ANGPTL4

Clasen

Krusenstjerna-Hafstrøm

Vendelbo

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org suppressed postprandial levels and increased activity during fasting and exercise. Following exposure to a physiological intravenous GH bolus, distinctive temporal changes in substrate fl uxes are recorded in skeletal muscle, characterized by reversible suppression of glucose uptake that peaks after 2 h together with increased uptake of lipids ( 2 ). Triglycerides (TG) in lipoproteins are hydrolyzed to FFA by lipoprotein lipase (LPL) before entering the muscle cell ( 3 ). Interestingly, GH treatment downregulates LPL activity ( 4 ), and hypersecretion of GH as seen in acromegaly is associated with hypertriglyceridemia ( 5 ). It has been shown in humans that GH stimulates turnover and oxidation of free fatty acids (FFA) together with unaltered VLDL-TG kinetics ( 6 ). This fi nding suggests that circulating FFA rather than VLDL-TG constitutes the major source for increased lipid metabolism in muscle following GH stimulation, but the mechanisms that regulate these processes are unknown.Experimental data in human subjects suggest that these insulin-antagonistic effects of GH, i.e., suppression of glucose uptake and stimulation of FFA, are causally linked, as pharmacological antilipolysis resulting in suppressed FFA levels abrogates GH-induced insulin resistance during a glucose clamp ( 7 ). In animal models and cell cultures, this is associated with inhibition of the IRS1-Akt pathway in muscle ( 8 ) and fat ( 9 ). However, in human subjects, GHinduced insulin resistance does not translate into suppression of pertinent insulin signaling pathways as assessed by

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Section: Discussionsupporting

confidence: 78%

Gene expression in skeletal muscle after an acute intravenous GH bolus in human subjects: identification of a mechanism regulating ANGPTL4

Clasen

Krusenstjerna-Hafstrøm

Vendelbo

et al. 2013

Journal of Lipid Research

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“…These findings suggest two possible scenarios: (1) that PI(3)P is produced by alternative sources such as the class II PI3Ks (Devereaux et al, 2013;Falasca and Maffucci, 2012;Posor et al, 2013); and/or (2) that a compensatory mechanism independent of PI(3)P is triggered to cope with the loss of Vps34. Previous reports indicate that expression of the constitutively active mutant of Rab5 can bypass the loss of EEA1 membrane localization upon wortmannin treatment Simonsen et al, 1998), and that wortmannin activates Rab5 (Chen and Wang, 2001).…”

Section: ) In Vps34mentioning

confidence: 96%

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

Jaber

Mohd-Naim

Wang

et al. 2016

Journal of Cell Science

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The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI (3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34 −/− mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells. The hyperactivation of Rab7 in Vps34-deficient cells stemmed from the failure to recruit the Rab7 GTPase-activating protein (GAP) Armus (also known as TBC1D2), which binds to PI(3)P, to late endosomes. Protein-lipid overlay and liposome-binding assays reveal that the putative pleckstrin homology (PH) domain in Armus can directly bind to PI(3)P. Elevated Rab7-GTP led to the failure of intraluminal vesicle (ILV) formation and lysosomal maturation. Rab7 silencing and Armus overexpression alleviated the vacuolization seen in Vps34-deficient cells. Taken together, these results demonstrate that Vps34 has a previously unknown role in regulating Rab7 activity and late endosomal trafficking.

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“…PI(3)P is also known to be generated in the PM. In adipocytes, PI(3)P is generated in the PM upon insulin stimulation and facilitates the translocation of the glucose transporter GLUT4 to the PM (60,61). In HeLa cells, PI(3)P is generated in the PM in response to lysophosphatidic acid and stimulates cell migration (62).…”

Section: Discussionmentioning

confidence: 99%

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

113

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Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P 3 and PI(3,4) P 2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca 2+ -activated K + channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

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Regulation and cellular functions of class II phosphoinositide 3-kinases

Cited by 139 publications

References 98 publications

Gene expression in skeletal muscle after an acute intravenous GH bolus in human subjects: identification of a mechanism regulating ANGPTL4

Gene expression in skeletal muscle after an acute intravenous GH bolus in human subjects: identification of a mechanism regulating ANGPTL4

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

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