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Phosphatidyl inositol 3'kinase-related kinases (PIKK) family

Members of the phosphatidylinositol-3 kinase family can produce phospholipids after activation by growth factors and other factors. As a second messenger, they bind and activate different target cells, forming a complex signal cascade. It plays a central role in chemotaxis, survival, protein transportation, and glucose metabolism. Based on the detailed classification and structural characteristics of phosphatidylinositol-3 kinase family members, the phosphatidylinositol-3 kinase-dependent signaling pathway and its related functions are introduced.

Phosphatidyl inositol 3'kinase-related kinases (PIKK) familyFigure 1. Phosphatidylinositol-4,5-bisphosphate 3-kinase.

Classification

According to different structures, specific substrates and regulatory subunits, the PI3K family can be divided into 3 major classes I. A heterodimer composed of a catalytic subunit with a molecular weight of 110 to 120 Daltons and a regulatory subunit with a molecular weight of 50 to 100 Daltons. There are four subtypes of catalytic subunits: p110α, p110β, p110γ, and p110δ. The regulated subunits are p50, p55, p85, and p1014 subtypes. Phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5 diphosphate can be phosphorylated in vitro; the only substrate in the body is phosphatidylinositol 4,5 diphosphate. Its activation is controlled by the binding of extracellular signal receptors to intracellular protein tyrosine kinases, Src-like protein tyrosine kinase coupling receptors, and G protein-coupled receptors.

Class I PI3K

Type I PI3K includes four different catalytic subunits, all with molecular weights around 110 Daltons, and have similar structural characteristics and specific substrates. In vitro, Class I PI3K can phosphorylate phosphatidylinositol to phosphatidylinositol triphosphate, phosphatidylinositol triphosphate to phosphatidylinositol 3,4 diphosphate, phosphatidylinositol 4,5 diphosphate to phospholipids Inositol 3,4,5 triphosphate. Type I PI3K usually exists in the cytoplasm in a resting state. After being stimulated by related receptors or adaptor proteins, it is recruited to ectopic to the cell membrane. It mainly acts on the cell membrane, but it has also been reported to act on intracellular vesicles and nuclei. According to different regulatory subunits and activation mechanisms, class I PI3K can be divided into two groups. Groups that can bind p85 and directly phosphorylate tyrosine residues are group 1A, while PI3Kγ and p101 proteins are group 1B.

Class II PI3K

Type II PI3K is recognized as a new type of PI3K because of its unique C-terminal C2 functional domain, and its molecular weight is usually between 170 and 210 Daltons. Class II PI3K does not bind to p85, and its regulatory subunits are not seen. According to the sequence of the N-terminal SH3 domain and the difference in sensitivity to wortmannin, class II PI3K can be divided into three groups, PI3K-C2α, PI3K-2Cβ, and PI3K-2Cγ. Type II PI3K is largely distributed in the cell membrane. Organelle membrane and even nuclear membrane. Extracellular signals such as integrin, growth factors, and chemokines can stimulate class II PI3K activation. In vitro, class II PI3K can phosphorylate phosphatidylinositol and phosphatidylinositol tetraphosphate, but cannot phosphorylate phosphatidylinositol 4,5 diphosphate. Type II PI3K does not have independent regulatory subunits, but it has C-terminal and N-terminal similar to type I PI3K to perform regulatory functions. The N-terminus does not have an independent structural functional domain, but has a coiled-coil structure and a proline-rich motif, thereby regulating protein-protein interactions. The C-terminus contains PX and C2 domains, which can regulate lipid or protein interactions on the cell membrane. The C2 domain is related to synaptic binding proteins. When its conserved aspartic acid residue is deleted, it is insensitive to Ca2+.

Class III PI3K

The prototype of class III PI3K is the Vps34p protein of the Vps34 gene product in Saccharomyces cerevisiae. All class III PI3K proteins only phosphorylate phosphatidylinositol to phosphatidylinositol 3-phosphate. The PIK3-C3 gene is located in the long arm 1 region 2 of chromosome 18, and includes a regulatory subunit with a molecular weight of 150 Daltons. It has endogenous serine protein kinase activity. Vac34-deficient yeast cells or Vps34-catalyzed cells failed to produce vacuolar sorting proteins. In these cells, phosphatidylinositol triphosphate was completely deleted, suggesting that Vps34p is the only protein with PI3K activity in yeast cells. In addition, Vps34 is mainly localized on the membrane of organelles and is related to autophagy and phagosome formation, internal vesicle formation, and nuclear membrane transport.

Distribution of PI3K

The study found that p110α and p110β are distributed in all tissues of the animal's body, p110γ is mainly distributed in white blood cells, p110δ is highly expressed in white blood cells, and also expressed at high levels in cancer cells, and p85α is distributed in various tissues of the animal's whole body. But its expression in skeletal muscle is the lowest, p55α is only distributed in the brain and muscle, p50α is mainly distributed in the liver, kidney and brain, and p85β is distributed in all tissues throughout the body, but its expression is the lowest in skeletal muscle. p55γ is highly expressed in the brain and testis, but not in liver and muscle. p101 is mainly expressed in white blood cells, p84 and p87 are highly expressed in white blood cells and myocardium, and PI3K-C2α is mainly distributed in myocardium, placenta and ovary. PI3K-C2β is mainly distributed in the thymus and placenta, and PI3K-C2γ is mainly distributed in the liver, prostate, breast and salivary glands.

Reference

  1. Kalaany NY; et al. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009, 458 (7239): 725-31.