Class III PI 3-kinase

Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation.

There is only one known class III PI 3-kinase, Vps34, which is also the only PI 3-kinase expressed in all eukaryotic cells. In humans it is encoded by the PIK3C3 gene. In human cells Vps34 associates with a regulatory subunit, p150.^[1]

Substrate specificity

Vps34 is more accurately described as a phosphatylinositol 3-kinase. In vivo Vps34 can phosphorylate only Phosphatidylinositol to form phosphatidylinositol (3)-phosphate (PtdIns(3)P).

Functions

Vps34 was first identified in a Saccharomyces cerevisiae (budding yeast) screen for proteins involved vesicle-mediated vacuolar protein sorting (hence Vps). A number of proteins containing a phosphoinositide binding domain specific for PtdIns(3)P that function in cellular protein trafficking have been identified.

Vps34 has been shown to interact with Vps15, a protein kinase. Vps15 can activate the lipid kinase activity of Vps34 and interact with Rab5, which has been hypothesized to recruit the Vps34/15 complex to early endosomes. Vps15 has a myristoylation tag that associates the complex with the membrane. The Vps34/15 complex also can interact with Rab7. Together, the complex can function at early to late endosomes.

Vps34 has a calmodulin binding domain, but its activity has been clearly shown to be calcium-independent in vitro and in vivo. The functional role of its interactions with calmodulin in vivo are not understood.

Vps34 activity is required for autophagy in yeast, and has been strongly implicated in this process in mammals. Vps34 has also been implicated in amino acid sensing. Vps34 is necessary for mTORC1 activity in response to amino acids in cultured cells, as siRNA knockdown completely inhibits mTORC1 signaling as determined by S6K phosphorylation. Sequestration of the Vps34 product by FYVE domain overexpression also disrupts mTOR signaling. However, genetic ablation of Vps34 in Drosophila does not affect dTORC1 signaling. Thus, the role of Vps34 in amino acid signaling to mTORC1 remains controversial.

One recent paper suggested that the human ortholog is regulated by intracellular calcium, but this was later shown to be due to a calcium-independent inhibition of Vps34 by EGTA, an effect not seen with other calcium chelators.

The mechanisms that regulate Vps34 activity in mammalian cells are not yet understood.

References

↑ Backer, J.M. (2008). "The regulation and function of Class III PI3Ks: novel roles for Vps34". Biochem. J. 410: 1–17.

Literature

Stein RC( 2001) Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment Endocr Relat Cancer 8:237-248
Foster FM, Traer CJ, Abraham SM, and Fry MJ (2003) The phosphoinositide (PI) 3-kinase family J Cell Sci 116:3037-3040.
Vanhaesebroeck B, Waterfield MD.(1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 253(1):239-54.

Transferases: phosphorus-containing groups (EC 2.7)

2.7.1-2.7.4:
phosphotransferase/kinase
(PO₄)

2.7.1: OH acceptor	Hexo- Gluco- Fructo- Hepatic Galacto- Phosphofructo- 1 Liver Muscle Platelet 2 Riboflavin Shikimate Thymidine ADP-thymidine NAD⁺ Glycerol Pantothenate Mevalonate Pyruvate Deoxycytidine PFP Diacylglycerol Phosphoinositide 3 Class I PI 3 Class II PI 3 Sphingosine Glucose-1,6-bisphosphate synthase

2.7.2: COOH acceptor	Phosphoglycerate Aspartate kinase

2.7.3: N acceptor	Creatine

2.7.4: PO₄ acceptor	Phosphomevalonate Adenylate Nucleoside-diphosphate Uridylate Guanylate Thiamine-diphosphate

2.7.6: diphosphotransferase
(P₂O₇)

2.7.7: nucleotidyltransferase
(PO₄-nucleoside)

Polymerase

DNA polymerase	DNA-directed DNA polymerase I II III IV V RNA-directed DNA polymerase Reverse transcriptase Telomerase DNA nucleotidylexotransferase/Terminal deoxynucleotidyl transferase

RNA nucleotidyltransferase	RNA polymerase/DNA-directed RNA polymerase RNA polymerase I RNA polymerase II RNA polymerase III RNA polymerase IV Primase RNA-dependent RNA polymerase PNPase

Phosphorolytic
3' to 5' exoribonuclease

Nucleotidyltransferase

Guanylyltransferase

mRNA capping enzyme

Other

2.7.8: miscellaneous

Phosphatidyltransferases	CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase CDP-diacylglycerol—serine O-phosphatidyltransferase CDP-diacylglycerol—inositol 3-phosphatidyltransferase CDP-diacylglycerol—choline O-phosphatidyltransferase

Glycosyl-1-phosphotransferase	N-acetylglucosamine-1-phosphate transferase

2.7.10-2.7.13: protein kinase
(PO₄; protein acceptor)

2.7.10: protein-tyrosine	see tyrosine kinases

2.7.11: protein-serine/threonine	see serine/threonine-specific protein kinases

2.7.12: protein-dual-specificity	see serine/threonine-specific protein kinases

2.7.13: protein-histidine	Protein-histidine pros-kinase Protein-histidine tele-kinase Histidine kinase

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

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Class III PI 3-kinase

Substrate specificity

Functions

See also

References

Literature