Role of class II phosphoinositide 3-kinase in cell signalling

Falasca, Marco; Maffucci, Tania

doi:10.1042/bst0350211

Cited by 93 publications

(77 citation statements)

References 43 publications

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“…Notably, in vitro studies demonstrated that PtdIns is the preferred target of class II PI3K, although this kinase also displays activity toward PtdIns4P. 161 It is therefore plausible that class II PI3K is a contributor to the PtdIns3P pool in addition to class III PtdIns3K. In support of this hypothesis, there is emerging evidence that class II PI3K is a significant producer of PtdIns3P, and class II PI3K holds a wide spectrum of functions ranging from cell signaling, to cell migration and vesicle trafficking.…”

Section: Regulation Of Autophagy By Pik3c3 Via Other Interacting Partmentioning

confidence: 99%

“…In support of this hypothesis, there is emerging evidence that class II PI3K is a significant producer of PtdIns3P, and class II PI3K holds a wide spectrum of functions ranging from cell signaling, to cell migration and vesicle trafficking. [161][162][163][164][165][166] One hint implying a role of class II PI3K in autophagy was provided by the studies on cell corpse clearance by phagocytosis in C. elegans. 167,168 In this process, autophagy is required for phagosome maturation and clearance of apoptotic cells; most importantly, class II PI3K was identified as a complementary kinase producing PtdIns3P on phagosomes, indispensable for the degradation of cell corpses in C. elegans.…”

Section: Regulation Of Autophagy By Pik3c3 Via Other Interacting Partmentioning

confidence: 99%

“…In response to pan-PI3K inhibitors, PIK3C2B and PIK3C2G exhibit similar sensitivity to wortmannin as class I PI3Ks and class III PtdIns3Ks, but PIK3C2A only responds to higher doses of wortmannin and LY294002. 161,166 Several inhibitors that demonstrate increased effectivity and selectivity toward specific isoforms of class II PI3Ks have been described recently, 188,189 offering hope for developing more selective inhibitors of class II PI3Ks. Since this class of PI3Ks is equally important in malignant transformation and carcinogenesis, 161,175 finding specific and effective class II PI3K inhibitors are among the important research goals for cell signaling studies and cancer treatment.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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Section: Regulation Of Autophagy By Pik3c3 Via Other Interacting Partmentioning

confidence: 99%

Section: Regulation Of Autophagy By Pik3c3 Via Other Interacting Partmentioning

confidence: 99%

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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“…The active site lysine (Lys802 in p110α and Lys833 in p110γ) is critical for catalysis and is highly conserved in lipid and protein kinases. Wortmannin also targets class II PI3K C2β (IC 50 =1.6 nM), the human class III PI3K hVps34p (IC 50 = 2.5 nM), type III PI4Ks (IC 50 =50-300 nM) and polo-like protein kinases that regulate mitosis (IC 50 =24-48 nM) [60][61][62][63][64]. Not surprisingly, considering the similarity between the PI3K and PIKK catalytic domains, wortmannin also irreversibly inhibits PIKK family members.…”

Section: Mtor Kinase Inhibitorsmentioning

confidence: 99%

“…In addition, use of immobilized LY294002 showed that the drug binds tightly to numerous non-kinase proteins with diverse functions, with as yet unknown biological consequences [80]. Class II PI3Ks (IC 50 =6.9-19 μM) and PI4Ks are relatively resistant to LY294002 as compared with the class I enzymes [60,61]. By contrast, the PIKK family members SMG-1, DNA-PK, and mTOR are targeted at low micromolar concentrations that also inhibit class I PI3Ks [41,65,82,83].…”

Section: Mtor Kinase Inhibitorsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

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Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

Botelho

2009

BioEssays

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Joining an antagonistic phosphoinositide (PtdInsP) kinase and phosphatase into a single protein complex may regulate rapid and local PtdInsP changes. This may be important for processes such as membrane fission that require a specific PtdInsP and that are innately local and rapid. Such a complex could couple vesicle formation, with erasing of the identity of the donor organelle from the vesicle prior to its fusion with target organelles, thus preventing organelle identity intermixing. Coordinating signals are postulated to switch the relative activities of the kinase and phosphatase in a spatio-temporal manner that matches membrane fission events. The discovery of two such complexes supports this hypothesis. One regulates the interconversion of phosphatidylinositol and PtdIns(3)P by joining the Vps34 PtdIns 3-kinase and the myotubularin 3-phosphatases. The other regulates the interconversion between PtdIns(3)P and PtdIns(3,5)P(2) through the Fab1/PIKfyve kinase and the Fig4/mFig4 phosphatase. These lipids are essential components of the endosomal identity code.

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Role of class II phosphoinositide 3-kinase in cell signalling

Cited by 93 publications

References 43 publications

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Rapamycin and mTOR kinase inhibitors

Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

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