Class III PI 3-kinase is a subgroup of the enzyme family,

phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

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 Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

cells. In humans it is encoded by the

PIK3C3 Phosphatidylinositol 3-kinase catalytic subunit type 3 is an enzyme subunit that in humans is encoded by the ''PIK3C3'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of ...

gene. In human cells Vps34 associates with a regulatory subunit, PIK3R4(p150, Vps15).

Substrate specificity

Vps34 is more accurately described as a phosphatidylinositol 3-kinase. ''In vivo'' Vps34 can phosphorylate only

phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

to form phosphatidylinositol (3)-phosphate (

PtdIns(3)P Phosphatidylinositol 3-phosphate (PtdIns3''P'') is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and II ...

Functions

Vps34 was first identified in a ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...

'' (budding yeast) screen for proteins involved vesicle-mediated vacuolar protein sorting (hence Vps). A number of proteins containing a

phosphoinositide binding domain Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

specific for PtdIns(3)P that function in cellular protein trafficking have been identified. Vps34 has been shown to interact with Vps15 (PIK3R4, p150), 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

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...

s. Vps15 has a

myristoylation Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. Myristic acid is a 14-carbon saturated fatty ac ...

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 Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...

in vivo are not understood. Vps34 activity is required for

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

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 Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating ...

knockdown completely inhibits mTORC1 signaling as determined by

S6K Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of Phosp ...

phosphorylation. Sequestration of the Vps34 product by

FYVE domain In molecular biology the FYVE zinc finger domain is named after the four cysteine-rich proteins: Fab 1 (yeast orthologue of PIKfyve), YOTB, Vac 1 (vesicle transport protein), and EEA1, in which it has been found. FYVE domains bind phosphatidylin ...

overexpression also disrupts mTOR signaling. However, genetic ablation of Vps34 in ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

'' 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 EGTA may refer to: * EGTA (chemical) EGTA (ethylene glycol-bis(β-aminoethyl ether)-''N'',''N'',''N''′,''N''′-tetraacetic acid), also known as egtazic acid ( INN, USAN), is an aminopolycarboxylic acid, a chelating agent. It is a white soli ...

, an effect not seen with other calcium chelators. The mechanisms that regulate Vps34 activity in mammalian cells are not yet understood.

References

Literature

*Stein RC( 2001) Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment ''Endocr Relat Cancer'' 8:237-24

*Foster FM, Traer CJ, Abraham SM, and Fry MJ (2003) The phosphoinositide (PI) 3-kinase family ''J Cell Sci'' 116:3037-304

*Vanhaesebroeck B, Waterfield MD.(1999) Signaling by distinct classes of phosphoinositide 3-kinases. ''Exp Cell Res.'' 253(1):239-5

{{Portal bar, Biology, border=no EC 2.7.1

Substrate specificity

Functions

See also

References

Literature