Class IA PI3K p110β Subunit Promotes Autophagy through Rab5 Small GTPase in Response to Growth Factor Limitation

Dou, Zhixun; Pan, Jinyan; Dbouk, Hashem A.; Ballou, Lisa M.; DeLeon, Jennifer L.; Fan, Ying; Chen, Juei Suei; Liang, Zong-Qi; Li, Guangpu; Backer, Jonathan M.; Lin, Richard Z.; Zong, Wei Xing

doi:10.1016/j.molcel.2013.01.022

Cited by 108 publications

(111 citation statements)

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“…Kinaseindependent roles have been described for other PI3Ks (Ciraolo et al, 2008;Dou et al, 2013). To determine whether the defects observed in Vps34 −/− MEFs are specific consequences of the loss of Vps34 kinase activity, we expressed HA-tagged Vps34 or a kinasedead mutant of Vps34, K771A, that fails to interact with the phosphoinositide substrate (Miller et al, 2010) …”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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 p110c and p110d isoforms are mainly restricted to functions in immune cells where they are expressed, whereas p110a and p110b are ubiquitous, but also exhibit isoform-specific cell-type-and context-dependent requirements. Most class I PI3K functions are related to their catalytic properties; however, there is growing evidence for kinaseindependent scaffolding roles for p110c and p110b (Patrucco et al, 2004;Hirsch et al, 2009;Dou et al, 2010;Rauch et al, 2011;Dou et al, 2013). Less well understood are the roles for the numerous regulatory adaptor isoforms in the regulation of class I p110 functions.…”

Section: Class I Pi3ksmentioning

confidence: 99%

Classes of phosphoinositide 3-kinases at a glance

Jean

Kiger

2014

Journal of Cell Science

302

247

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The phosphoinositide 3-kinase (PI3K) family is important to nearly all aspects of cell and tissue biology and central to human cancer, diabetes and aging. PI3Ks are spatially regulated and multifunctional, and together, act at nearly all membranes in the cell to regulate a wide range of signaling, membrane trafficking and metabolic processes. There is a broadening recognition of the importance of distinct roles for each of the three different PI3K classes (I, II and III), as well as for the different isoforms within each class. Ongoing issues include the need for a better understanding of the in vivo complexity of PI3K regulation and cellular functions. This Cell Science at a Glance article and the accompanying poster summarize the biochemical activities, cellular roles and functional requirements for the three classes of PI3Ks. In doing so, we aim to provide an overview of the parallels, the key differences and crucial interplays between the regulation and roles of the three PI3K classes.

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“…69 Subsequently, it was found that upon growth factor withdrawal, PIK3CB dissociates from the growth receptor complex and interacts with RAB5A/RAB5, keeping this small GTPase in the GTP-bound state. 70 GTP-loaded RAB5A plays a role in the activation of PIK3C3. 71 Through association with RAB5A, PIK3CB enhances PIK3C3 activity and promotes autophagy.…”

Section: Regulation Of Autophagy By Class I Pi3ksmentioning

confidence: 99%

“…71 Through association with RAB5A, PIK3CB enhances PIK3C3 activity and promotes autophagy. 70 In contrast to the class I PI3K holokinases, which carry the signals from growth factors and indirectly curb autophagy, the PIK3CB subunit acts as a sensor of growth factor availability and stimulates autophagy under circumstances of growth factor limitation.…”

Section: Regulation Of Autophagy By Class I Pi3ksmentioning

confidence: 99%

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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Class IA PI3K p110β Subunit Promotes Autophagy through Rab5 Small GTPase in Response to Growth Factor Limitation

Cited by 108 publications

References 47 publications

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

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

Classes of phosphoinositide 3-kinases at a glance

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

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