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Literature summary for 2.7.1.137 extracted from

  • Backer, J.M.
    The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34 (2016), Biochem. J., 473, 2251-2271 .
    View publication on PubMed

Activating Compound

Activating Compound Comment Organism Structure
additional information Beclin-limited model of Vps34 activation, overview. Activation of Vps34 during autophagy involves the regulated assembly of Vps34 Complex I and Complex II, driven by the release of sequestered Beclin-1 to form complexes with Vps34, Vps15 and either Atg14 or UVRAG. The availability of Beclin-1 is rate-limiting for the formation of productive Vps34 complexes Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information phenotypes in knockout Vps34 mice: cardiomegaly, decreased contractility of the heart, reduced progression to maladaptive cardiac hypertrophy, impaired myoblast differentiation, murine muscular dystrophy, proteinuria, glomerular scarring, loss of dendritic spines, neurodegeneration, vacuolization in large diameter sensory neurons, increased lysosomes in small diameter neurons, neurodegeneration, increased amyloidogenic processing of amyloid precursor protein (APP), reduced sorting of APP to MVBs, reduced T-cell number, increased cell death and reduced IL-7 receptor expression, reduced T-cell survival, increased mitochondrial mass and ROS, reduced natural killer (NK) cells, and inflammatory wasting syndrome with reduced CD4+ Foxp3+ regulatory T-cells (Tregs) Mus musculus
S90A site-directed mutagenesis, basal Beclin-1-associated Vps34 activity is decreased in cells expressing S90A Beclin-1, and increased in cells expressing S90E Beclin-1 Homo sapiens
S90E site-directed mutagenesis, basal Beclin-1-associated Vps34 activity is decreased in cells expressing S90A Beclin-1, and increased in cells expressing S90E Beclin-1 Homo sapiens
Y231F Vps34 is activated in Src-transformed cells by phosphorylation at Tyr231 and Tyr310, and kinase-dead or Y231F Vps34 blocks Src-mediated transformation. Expression of Y231F Vps34 causes a reduction in insulin-stimulated activation of S6K1 Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(8S)-2-[(3R)-3-methylmorpholin-4-yl]-9-(3-methyl-2-oxobutyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
-
Homo sapiens
3-Methyladenine
-
Homo sapiens
GDC-0941
-
Homo sapiens
PI-103
-
Homo sapiens
PIK-III
-
Homo sapiens
SAR405
-
Homo sapiens
Vps34-IN-1
-
Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
endoplasmic reticulum
-
Saccharomyces cerevisiae 5783
-
endoplasmic reticulum
-
Homo sapiens 5783
-
endoplasmic reticulum
-
Mus musculus 5783
-
endosome
-
Saccharomyces cerevisiae 5768
-
endosome
-
Homo sapiens 5768
-
endosome
-
Mus musculus 5768
-
phagosome
-
Saccharomyces cerevisiae
-
-
phagosome
-
Homo sapiens
-
-
phagosome
-
Mus musculus
-
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+
-
Saccharomyces cerevisiae
Mg2+
-
Homo sapiens
Mg2+ required Mus musculus

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + 1-phosphatidyl-1D-myo-inositol Saccharomyces cerevisiae
-
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol Homo sapiens
-
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol Mus musculus
-
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q8NEB9
-
-
Mus musculus Q6PF93
-
-
Saccharomyces cerevisiae P22543
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein for Vps34, phosphorylation sites within the C2 domain are inhibitory (Thr159, Thr163 and Ser165) as is phosphorylation of Thr668 in the kinase domain. Activating phosphorylation sites are in the C2-helical linker (Tyr231) or in the kinase domain (Tyr310 and Thr667). Inhibitory phosphorylation sites in Atg14 (Ser3, Ser223, Ser233, Ser383 and Ser440) are spread throughout the proteins. Ser90 phosphorylation regulates Vps34 activity Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
heart
-
Mus musculus
-
hippocampus
-
Mus musculus
-
kidney
-
Mus musculus
-
neuron pyramidal neurons, sensory neurons, and cortical neurons Mus musculus
-
podocyte
-
Mus musculus
-
skeletal muscle
-
Mus musculus
-
T-lymphocyte
-
Mus musculus
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + 1-phosphatidyl-1D-myo-inositol
-
Saccharomyces cerevisiae ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol
-
Homo sapiens ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol
-
Mus musculus ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol phosphorylation of phosphatidylinositol at the 3'-position on the inositol ring Saccharomyces cerevisiae ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?
ATP + 1-phosphatidyl-1D-myo-inositol phosphorylation of phosphatidylinositol at the 3'-position on the inositol ring Homo sapiens ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
?

Synonyms

Synonyms Comment Organism
class III phosphoinositide 3-kinase
-
Saccharomyces cerevisiae
class III phosphoinositide 3-kinase
-
Homo sapiens
class III phosphoinositide 3-kinase
-
Mus musculus
vacuolar protein sorting 34
-
Saccharomyces cerevisiae
vacuolar protein sorting 34
-
Homo sapiens
vacuolar protein sorting 34
-
Mus musculus
VPS34
-
Saccharomyces cerevisiae
VPS34
-
Homo sapiens
VPS34
-
Mus musculus

Cofactor

Cofactor Comment Organism Structure
ATP
-
Saccharomyces cerevisiae
ATP
-
Homo sapiens
ATP
-
Mus musculus

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000012
-
pH and temperature not specified in the publication Homo sapiens SAR405
0.000002
-
pH and temperature not specified in the publication Homo sapiens (8S)-2-[(3R)-3-methylmorpholin-4-yl]-9-(3-methyl-2-oxobutyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one
0.000018
-
pH and temperature not specified in the publication Homo sapiens PIK-III
0.000025
-
pH and temperature not specified in the publication Homo sapiens Vps34-IN-1
0.000036
-
pH and temperature not specified in the publication Homo sapiens 3-Methyladenine
0.000488
-
pH and temperature not specified in the publication Homo sapiens PI-103
0.01
-
above, pH and temperature not specified in the publication Homo sapiens GDC-0941

General Information

General Information Comment Organism
evolution vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals Mus musculus
evolution vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals. The domain organization of Vps34 and Vps15 are highly conserved between yeast and humans Saccharomyces cerevisiae
evolution vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals. The domain organization of Vps34 and Vps15 are highly conserved between yeast and humans Homo sapiens
malfunction consistent with a regulatory role for Ser90 phosphorylation, induction of autophagy by amino acid starvation is reduced in cells expressing S90A Beclin-1 Homo sapiens
malfunction PARQ3 knockdown in cells or knockout in mice leads to reductions in Atg14-associated Beclin-1, Vps34 and Vps15 Mus musculus
metabolism regulation by accessory proteins for Vps34 Complex I and II, and regulation of Vps34 complexes by phosphorylation during starvation, mechanisms, overview. In yeast, targeting of Vps34 to the pre-autophagosomal structure (PAS) requires Atg14 (although targeting of Vps15 to the PAS is Atg14-independent) Saccharomyces cerevisiae
metabolism regulation by accessory proteins for Vps34 Complex I and II, e.g. Beclin-1, mechanisms, overview. Members of Vps34 Complex I and II are regulated by a number of selective degradation systems. Regulation of Vps34 complexes by phosphorylation during starvation, overview Homo sapiens
metabolism regulation of Vps34 complexes by phosphorylation during starvation, overview Mus musculus
additional information domain organization of yeast Vps30, Atg14 and Vps38, structures of Complex I and II, crystal structure analysis of yeast Vps34 Complex II, overview Saccharomyces cerevisiae
additional information the major domains of Vps34 are found in all PI3Ks, and include a C2 domain, a helical domain and a kinase domain. Vps15 contains an N-terminally myristoylated kinase-like domain, a helical domain containing a series of internal HEAT [huntingtin, elongation factor 3, the PR65/A subunit of protein phosphatase 2A and TOR (target of rapamycin)] repeats and a C-terminal WD40 domain that forms a beta-propeller structure. The kinase domain has an atypical ATP-binding site. Domain organization of mammalian Vps34, Vps15, Beclin-1, Atg14 and UVRAG, structures of Complex I and II, cryo-EM structure of human Vps34 Complex I, overview Homo sapiens
physiological function the Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Vps34 acts in a complex with a probable pseudokinase, Vps15, and signals to downstream effectors through the production of phosphatidylinositol 3-phosphate (PI[3]P). This lipid supplies a binding site for proteins containing appropriate lipid-binding domains, e.g. FYVE [Fab1, YOTB, Vac1, EEA1 (early endosomal antigen 1)] and PX (Phox homology) domain. Vps34 is recruited by the binding of the WD40 domain of Vps15 to activated Rab5. Production of PI[3]P synergizes with Rab5 in the recruitment of EEA1 and Rabenosyn5 to drive endosomal tethering and fusion. Vps34-Vps15 also binds to Rab7 in late endosomess. Vps34 acts in tetrameric complexes containing Vps15, Beclin-1 and either Atg14 (Vps34 complex I) or UVRAG (Vps34 complex II). Vps34 acts by producing PI[3]P in intracellular membranes. Vps34 regulates the fusion and maturation of Rab5-positive early endosomes (EE) and their maturation into Rab7-positive late endosomes (LE). PI[3]P produced by Vps34 recruits the retromer complex, which mediates endosome to Golgi retrograde trafficking, and the ESCRT complex, which produces ILVs in multivesicular bodies (MVB). Vps34 is recruited to phagosomes after sealing to direct phagosomal maturation. It functions in the endoplasmic reticulum and in maturing autophagosomes, where it drives autophagosomal initiation and maturation. Vps34 is required for the function of the retromer complex, which drives the retrograde trafficking of endocytic cargo to the Golgi. Mechanisms of Vps34 regulation, e.g. by phosphorylation under nutrient-replete conditions or during growth factor stimulation. Vps34 can act as an upstream regulator of mTORC1 regulation Homo sapiens
physiological function the Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Vps34 acts in a complex with a probable pseudokinase, Vps15, and signals to downstream effectors through the production of phosphatidylinositol 3-phosphate (PI[3]P). This lipid supplies a binding site for proteins containing appropriate lipid-binding domains, e.g. FYVE [Fab1, YOTB, Vac1, EEA1 (early endosomal antigen 1)] and PX (Phox homology) domain. Vps34 is recruited by the binding of the WD40 domain of Vps15 to activated Rab5. Production of PI[3]P synergizes with Rab5 in the recruitment of EEA1 and Rabenosyn5 to drive endosomal tethering and fusion. Vps34-Vps15 also binds to Rab7 in late endosomess. Vps34 acts in tetrameric complexes containing Vps15, Beclin-1 and either Atg14 (Vps34 complex I) or UVRAG (Vps34 complex II). Vps34 acts by producing PI[3]P in intracellular membranes. Vps34 regulates the fusion and maturation of Rab5-positive early endosomes (EE) and their maturation into Rab7-positive late endosomes (LE). PI[3]P produced by Vps34 recruits the retromer complex, which mediates endosome to Golgi retrograde trafficking, and the ESCRT complex, which produces ILVs in multivesicular bodies (MVB). Vps34 is recruited to phagosomes after sealing to direct phagosomal maturation. It functions in the endoplasmic reticulum and in maturing autophagosomes, where it drives autophagosomal initiation and maturation. Vps34 is required for the function of the Retromer complex, which drives the retrograde trafficking of endocytic cargo to the Golgi. Mechanisms of Vps34 regulation, e.g. by phosphorylation under nutrient-replete conditions or during growth factor stimulation Saccharomyces cerevisiae