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
The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
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 has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is ...
gene. In human cells Vps34 associates with a regulatory subunit,
PIK3R4
Phosphoinositide 3-kinase regulatory subunit 4, also known as PI3-kinase regulatory subunit 4 or PI3-kinase p150 subunit or phosphoinositide 3-kinase adaptor protein, or ''VPS15'' is an enzyme that in humans is encoded by the ''PIK3R4'' gene
...
(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 is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
to form phosphatidylinositol (3)-phosphate (
PtdIns(3)P
Phosphatidylinositol 3-phosphate (PI3P) 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 III phosph ...
).
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 fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' (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 (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 the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
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 f ...
tag that associates the complex with the membrane. The Vps34/15 complex also can interact with
Rab7
Ras-related protein Rab-7a is a protein that in humans is encoded by the ''RAB7A'' gene.
Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the ...
. 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 Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
in vivo are not understood.
Vps34 activity is required for
autophagy
Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
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
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is comp ...
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 non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...
knockdown completely inhibits mTORC1 signaling as determined by
S6K 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 phosphatidyli ...
overexpression also disrupts mTOR signaling. However, genetic ablation of Vps34 in ''
Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
'' 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.
See also
*
PX domain
References
Literature
*
*
*
{{Portal bar, Biology, border=no
EC 2.7.1