Gene Symbol: Pik3c3
Description: phosphatidylinositol 3-kinase catalytic subunit type 3
Alias: 5330434F23Rik, Vps34, phosphatidylinositol 3-kinase catalytic subunit type 3, PI3-kinase type 3, PI3K type 3, phosphoinositide-3-kinase, class 3, ptdIns-3-kinase type 3
Species: mouse
Products:     Pik3c3

Top Publications

  1. Lee A, States D. Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells. Cell Death Differ. 2006;13:1900-14 pubmed
    ..This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis. ..
  2. Kim J, Kim Y, Fang C, Russell R, Kim J, Fan W, et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell. 2013;152:290-303 pubmed publisher
    ..The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction...
  3. Jaber N, Dou Z, Chen J, Catanzaro J, Jiang Y, Ballou L, et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci U S A. 2012;109:2003-8 pubmed publisher
    A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive...
  4. Zhou X, Wang F. Effects of neuronal PIK3C3/Vps34 deletion on autophagy and beyond. Autophagy. 2010;6:798-9 pubmed
    b>PIK3C3/Vps34 plays important roles in the endocytic and autophagic pathways, both of which are essential for maintaining neuronal integrity...
  5. Zhou X, Takatoh J, Wang F. The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. PLoS ONE. 2011;6:e16358 pubmed publisher
    The Pik3c3 gene encodes an 887 amino acid lipid kinase, phosphoinositide-3-kinase class 3 (PIK3C3). PIK3C3 is known to regulate various intracellular membrane trafficking events...
  6. Parekh V, Wu L, Boyd K, Williams J, Gaddy J, Olivares Villagómez D, et al. Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34. J Immunol. 2013;190:5086-101 pubmed publisher
    ..However, recent studies have cast doubt on the role of Vps34 in autophagy, at least in certain cell types...
  7. Devereaux K, Dall Armi C, Alcazar Roman A, Ogasawara Y, Zhou X, Wang F, et al. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS ONE. 2013;8:e76405 pubmed publisher
    Synthesis of phosphatidylinositol-3-phosphate (PI3P) by Vps34, a class III phosphatidylinositol 3-kinase (PI3K), is critical for the initial steps of autophagosome (AP) biogenesis...
  8. Willinger T, Flavell R. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc Natl Acad Sci U S A. 2012;109:8670-5 pubmed publisher
    ..Genetic ablation in lower organisms has revealed a critical role for Vps34, an evolutionary conserved class III phosphoinositide-3 kinase (PI3K), in regulating endocytosis and autophagy; ..
  9. Fimia G, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, et al. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447:1121-5 pubmed

More Information


  1. Zhou X, Wang L, Hasegawa H, Amin P, Han B, Kaneko S, et al. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc Natl Acad Sci U S A. 2010;107:9424-9 pubmed publisher
    The lipid kinase PIK3C3 (also called Vps34) regulates both the endosomal and autophagic pathways. However, the effect of inactivating PIK3C3 on neuronal endosomal versus autophagic processes in vivo has not been studied...
  2. Morishita H, Eguchi S, Kimura H, Sasaki J, Sakamaki Y, Robinson M, et al. Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem. 2013;288:11436-47 pubmed publisher
    ..We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed ..
  3. McLeod I, Zhou X, Li Q, Wang F, He Y. The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7R? surface expression. J Immunol. 2011;187:5051-61 pubmed publisher
    ..However, how the intracellular process of IL-7R? trafficking is regulated is unclear. In this paper, we show that Vps34, the class III PI3K, plays a critical role in proper IL-7R? intracellular trafficking...
  4. Xia P, Wang S, Du Y, Zhao Z, Shi L, Sun L, et al. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J. 2013;32:2685-96 pubmed publisher
    ..The lysine 437 ubiquitination of Beclin 1 enhances the association with Vps34 to promote Vps34 activity...
  5. Jaber N, Mohd Naim N, Wang Z, Deleon J, Kim S, Zhong H, et al. Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus. J Cell Sci. 2016;129:4424-4435 pubmed
    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...
  6. Munson M, Allen G, Toth R, Campbell D, Lucocq J, Ganley I. mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO J. 2015;34:2272-90 pubmed publisher
    ..3-phosphate that, when depleted by specific inhibition of the class III phosphoinositide 3-kinase VPS34, results in prolonged lysosomal tubulation...
  7. Ikonomov O, Sbrissa D, Venkatareddy M, TISDALE E, Garg P, Shisheva A. Class III PI 3-kinase is the main source of PtdIns3P substrate and membrane recruitment signal for PIKfyve constitutive function in podocyte endomembrane homeostasis. Biochim Biophys Acta. 2015;1853:1240-50 pubmed publisher
    ..Whereas the PtdIns3P source is undetermined, class III PI3K (Vps34), the only evolutionarily conserved of the eight mammalian PI3Ks, is presumed as a main candidate...
  8. Bejarano E, Yuste A, Patel B, Stout R, Spray D, Cuervo A. Connexins modulate autophagosome biogenesis. Nat Cell Biol. 2014;16:401-14 pubmed publisher
    ..initial steps of autophagosome formation, such as Atg16 and components of the PI(3)K autophagy initiation complex (Vps34, Beclin-1 and Vps15)...
  9. He F, Agosto M, Anastassov I, Tse D, Wu S, Wensel T. Phosphatidylinositol-3-phosphate is light-regulated and essential for survival in retinal rods. Sci Rep. 2016;6:26978 pubmed publisher
    ..This increase was blocked in a rod-specific knockout of the PI-3 kinase Vps34, resulting in failure of endosomal and autophagy-related membranes to fuse with lysosomes, and accumulation of ..
  10. Logan A, Mammel A, Robinson D, Chin A, Condon A, Robinson F. Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling. Glia. 2017;65:1452-1470 pubmed publisher
    The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy...
  11. Nemazanyy I, Montagnac G, Russell R, Morzyglod L, Burnol A, Guan K, et al. Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling. Nat Commun. 2015;6:8283 pubmed publisher
    ..Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance. ..
  12. Tuhácková Z, Sloncova E, Vojtechova M, Sovová V. IL2-dependent phosphorylation of 40S ribosomal protein S6 is controlled by PI-3K/mTOR signalling in CTLL2 cells. Int J Mol Med. 2004;13:601-5 pubmed
    ..The data support the hypothesis that Akt may act downstream to PI-3K and upstream to mTOR in an IL2-mediated signal transduction pathway that controls phosphorylation of the regulatory protein S6 in CTLL2 cells. ..
  13. Zhang D, Zhang W, Li D, Fu M, Chen R, Zhan Q. GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3. Autophagy. 2015;11:2247-58 pubmed publisher
    ..Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in ..
  14. Lorenzo D, Badea A, Davis J, Hostettler J, He J, Zhong G, et al. A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport. J Cell Biol. 2014;207:735-52 pubmed publisher
    ..In this paper, we identify a new pathway based on the class III PI3-kinase (PIK3C3), ankyrin-B (AnkB), and dynactin, which promotes fast axonal transport of synaptic vesicles, mitochondria, ..
  15. Liu C, Lin Y, Chen Y, Chen C, Pang L, Chen H, et al. Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. Mol Cell. 2016;61:84-97 pubmed publisher
    ..Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism...
  16. Valet C, Levade M, Chicanne G, Bilanges B, Cabou C, Viaud J, et al. A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth. Blood. 2017;130:2032-2042 pubmed publisher
    To uncover the role of Vps34, the sole class III phosphoinositide 3-kinase (PI3K), in megakaryocytes (MKs) and platelets, we created a mouse model with Vps34 deletion in the MK/platelet lineage (Pf4-Cre/Vps34lox/lox)...
  17. Wang L, Budolfson K, Wang F. Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration. Neuroscience. 2011;172:427-42 pubmed publisher
    The lipid kinase PIK3C3 (also known as VPS34) regulates multiple aspects of endo-membrane trafficking processes. PIK3C3 is widely expressed by neurons in the CNS, and its catalytic product PI3P is enriched in dendritic spines...
  18. Yang Y, Fiskus W, Yong B, Atadja P, Takahashi Y, Pandita T, et al. Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. Proc Natl Acad Sci U S A. 2013;110:6841-6 pubmed publisher
    ..However, how autophagy-inducing stress regulates Vps34 activity has not been fully elucidated...
  19. Inaguma Y, Ito H, Iwamoto I, Matsumoto A, Yamagata T, Tabata H, et al. Morphological characterization of Class III phosphoinositide 3-kinase during mouse brain development. Med Mol Morphol. 2016;49:28-33 pubmed publisher
    The mammalian Class III phosphoinositide 3-kinase (PIK3C3, also known as mammalian vacuolar protein sorting 34 homologue, Vps34) is a regulator of vesicular trafficking, autophagy, and nutrient sensing...
  20. Reifler A, Li X, Archambeau A, McDade J, Sabha N, Michele D, et al. Conditional knockout of pik3c3 causes a murine muscular dystrophy. Am J Pathol. 2014;184:1819-30 pubmed publisher
    ..its production, and created a muscle-specific conditional knockout of the class III phosphatidylinositol 3-kinase, Pik3c3. Muscle-specific deletion of Pik3c3 did not disturb embryogenesis or early postnatal development, but resulted in ..
  21. Miranda A, Lasiecka Z, Xu Y, Neufeld J, Shahriar S, Simoes S, et al. Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nat Commun. 2018;9:291 pubmed publisher
    ..is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal ..
  22. Xu D, Wang Z, Wang C, Zhang D, Wan H, Zhao Z, et al. PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity. EMBO J. 2016;35:496-514 pubmed publisher
    The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation...
  23. Kuo C, Lin W, Liang C, Liang S. Class I and III phosphatidylinositol 3'-kinase play distinct roles in TLR signaling pathway. J Immunol. 2006;176:5943-9 pubmed
    ..These results suggest that class I and class III PI3K play distinct roles in not only the uptake of CpG ODN, but also responses elicited by CpG ODN and LPS. ..
  24. Yu P, Zhang Y, Li C, Li Y, Jiang S, Zhang X, et al. Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure. J Cell Mol Med. 2015;19:1710-9 pubmed publisher
    ..Secondly, activation of Class III PI3K Vacuolar protein sorting 34 (Vps34), as demonstrated by upregulation of Vps34 expression, increased interaction of Vps34 with Beclin-1, and deceased ..
  25. McKnight N, Zhong Y, Wold M, Gong S, Phillips G, Dou Z, et al. Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex. PLoS Genet. 2014;10:e1004626 pubmed publisher
    ..Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy ..
  26. Lu J, He L, Behrends C, Araki M, Araki K, Jun Wang Q, et al. NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity. Nat Commun. 2014;5:3920 pubmed publisher
    The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy...
  27. Bechtel W, Helmstädter M, Balica J, Hartleben B, Kiefer B, Hrnjic F, et al. Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J Am Soc Nephrol. 2013;24:727-43 pubmed publisher
    ..Here, we show that the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (Vps34) plays a central role in modulating endocytic pathways, maintaining podocyte homeostasis...
  28. Lin M, Liu H, Xiong Q, Niu H, Cheng Z, Yamamoto A, et al. Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase. Autophagy. 2016;12:2145-2166 pubmed
    ..type IV secretion effector protein, Etf-1, bound RAB5 and the autophagy-initiating class III PtdIns3K complex, PIK3C3/VPS34, and BECN1, and homed to ehrlichial inclusions...
  29. Kamda J, Singer S. Phosphoinositide 3-kinase-dependent inhibition of dendritic cell interleukin-12 production by Giardia lamblia. Infect Immun. 2009;77:685-93 pubmed publisher
    ..These data suggest that this parasite actively interferes with host innate immunity, resulting in an immune response able to control the infection but devoid of strong inflammatory signals. ..
  30. Parekh V, Pabbisetty S, Wu L, Sebzda E, Martinez J, Zhang J, et al. Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8?+ dendritic cells. Proc Natl Acad Sci U S A. 2017;114:E6371-E6380 pubmed publisher
    The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes...
  31. Chen J, Chen M, Fogo A, Harris R, Chen J. mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol. 2013;24:198-207 pubmed publisher
    ..In conclusion, these results demonstrate an indispensable role for mVps34 in the trafficking of intracellular vesicles to protect the normal cellular metabolism, structure, and function of podocytes. ..
  32. Guo L, Stripay J, Zhang X, Collage R, Hulver M, Carchman E, et al. CaMKI? regulates AMP kinase-dependent, TORC-1-independent autophagy during lipopolysaccharide-induced acute lung neutrophilic inflammation. J Immunol. 2013;190:3620-8 pubmed publisher
    ..Independently inhibiting autophagy, using siRNA targeting the PI3K VPS34, yielded similar reductions in lung autophagy and neutrophil recruitment...
  33. Ma X, Zhang S, He L, Rong Y, Brier L, Sun Q, et al. MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy. 2017;13:592-607 pubmed publisher
    ..III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood...
  34. Anderson K, Boyle K, Davidson K, Chessa T, Kulkarni S, Jarvis G, et al. CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of Escherichia coli or Staphylococcus aureus is regulated by class III but not class I or II PI3Ks. Blood. 2008;112:5202-11 pubmed publisher
    ..the oxidase was independent of class I and II PI3Ks, but substantially dependent on the single class III isoform (Vps34). Class III PI3K was responsible for the synthesis of PtdIns(3)P on phagosomes containing either bacteria...
  35. Su H, Yang F, Wang Q, Shen Q, Huang J, Peng C, et al. VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy. Mol Cell. 2017;67:907-921.e7 pubmed publisher
    The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy...
  36. Vicinanza M, Korolchuk V, Ashkenazi A, Puri C, Menzies F, Clarke J, et al. PI(5)P regulates autophagosome biogenesis. Mol Cell. 2015;57:219-34 pubmed publisher
    Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like WIPI2, during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy...
  37. Carpentier S, N kuli F, Grieco G, Van Der Smissen P, Janssens V, Emonard H, et al. Class III phosphoinositide 3-kinase/VPS34 and dynamin are critical for apical endocytic recycling. Traffic. 2013;14:933-48 pubmed publisher
    ..We first report three in vitro or in vivo evidences that class III PI3K/VPS34 is the key PI3K isoform regulating apical recycling...
  38. Sabha N, Volpatti J, Gonorazky H, Reifler A, Davidson A, Li X, et al. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models. J Clin Invest. 2016;126:3613-25 pubmed publisher
    ..Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of ..
  39. Bridges D, Ma J, Park S, Inoki K, Weisman L, Saltiel A. Phosphatidylinositol 3,5-bisphosphate plays a role in the activation and subcellular localization of mechanistic target of rapamycin 1. Mol Biol Cell. 2012;23:2955-62 pubmed publisher
    ..formation depends on the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2?, as well as the class III PI3K Vps34, while PI(3,5)P(2) requires the phosphatidylinositol-3-phosphate-5-kinase PIKFYVE...
  40. Yamada E, Bastie C, Koga H, Wang Y, Cuervo A, Pessin J. Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway. Cell Rep. 2012;1:557-69 pubmed publisher
    ..This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1...
  41. Cheng Z, Zhu Q, Dee R, Opheim Z, Mack C, Cyr D, et al. Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth. J Biol Chem. 2017;292:2065-2079 pubmed publisher
    ..This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux. ..
  42. Sir D, Tian Y, Chen W, Ann D, Yen T, Ou J. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A. 2010;107:4383-8 pubmed publisher
    ..Our studies thus demonstrate that a DNA virus can use autophagy to enhance its own replication and indicate the possibility of targeting the autophagic pathway for the treatment of HBV patients. ..
  43. Pozuelo Rubio M. Regulation of autophagic activity by 14-3-3? proteins associated with class III phosphatidylinositol-3-kinase. Cell Death Differ. 2011;18:479-92 pubmed publisher
    ..In this study, 14-3-3? proteins are shown as a negative regulator of autophagy through regulation of a key component of early stages of the autophagy pathway, such as hVps34. ..
  44. Ma C, Wang N, Detre C, Wang G, O Keeffe M, Terhorst C. Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex. J Biol Chem. 2012;287:18359-65 pubmed publisher
    ..that in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG...
  45. Virbasius J, Guilherme A, Czech M. Mouse p170 is a novel phosphatidylinositol 3-kinase containing a C2 domain. J Biol Chem. 1996;271:13304-7 pubmed
    ..Mouse p170 utilizes PI and to a limited extent PI 4-P as substrates, in contrast to the PI-specific yeast VPS34 homolog PtdIns 3-kinase and the p110 PI 3-kinases, which phosphorylate PI, PI 4-P, and PI 4,5-P2...
  46. Bilanges B, Alliouachene S, Pearce W, Morelli D, Szabadkai G, Chung Y, et al. Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism. Nat Commun. 2017;8:1804 pubmed publisher
    b>Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking...