Classes and Structure:
The PI3Ks are an ancient family of intracellular kinases that evolved to mediate nutrient sensing and metabolic control. In mammals, there are 8 different PI3K catlytic subunits, dviided into three classes. Class I PI3Ks phosphorylate phosphatidylinositol (,5)P2 (PIP2) to geenrate phosphatidylinositol (3,4,5)P3 (PIP3) which acts as pivotal second messenger signaling moleule. In B cells, both AKt and Btk can bind to PIP3 via their PH domains. PIP3 is essential for teh activaiton of Akt and contributes to the activation of Btk. Less is known about the role of classes II and III PI3Ks in B cells. (Okkenhaug, “PI3k signaling in normal B cells and chronic lymphocytic leukemia”, Current Topics in Microbiology and Immunology )2106) 393: 123-142).
Class I phosphoinositide 3-kinases (PI 3-kinases; PI3Ks):
Class I PI3Ks are of particualr interest and are futher divided into class IA and class IB kinases based on sequence homology and substrate specificity. Class IA PI3Ks contain a p85 regulatory subunit that therodimerizes with a p100, alpha, beta or delta catalytic subunit. These kinases are commonly known as PI3Kalpha, beta and delta respectiviely and are activated by receptor tyrosinekinases. The class IB PI3k contains a p110gamma ctalyti subunit and is commonly known as PI3kgamma which is activated by heterotrimeric G proteins. (Qiao, US 2012/0258967).
Mammals, have 4 differnt class I PI3Ks. Heterodimers of a regultory subunit (p85alpha, p55alpha, p50alpha, p85beta or p55gamme, collectively referred to as p85) and a catlytic subunit (p110alpha, p110beta or p110epsilon) form PI3kalpha, PI3kbeta or PI3kbeta wehreas PI3kgamma is a hterodimer of p101 or p84 with p110gamma. (Okkenhaug, “PI3k signaling in normal B cells and chronic lymphocytic leukemia”, Current Topics in Microbiology and Immunology )2106) 393: 123-142).
Structurally, class I PI3Ks exists as heterodimeric complexes, consisting of a p100 catalytic subunit and a p55, p85, or p101 regulatory subunit. There are four p110 catalytic subunits. Class I PI3Ks can be further divided into two subclasses (Ia and Ib) based on ther mechanism of action.
PI3 kinase is classified into three classes (iel, classes I-III) in terms of structure. Class I is further divided into classes IA adn 1B and of these, class IA is divided into three isotypes, p110alpha, p110beta adn p110epsilon (Niikura, US Patent Application No: 16/484,061, published as US 2019/0359691).
Functions:
PI3 Kinase (phosphoinositide 3-kinase: PI3K) phosphorylates the position 3 of the inositol ring of phosphatidylinositol, and plays an important role in various cellular functions such as cell survival, cell growth, cell motility, and the transport of intracellular organelle. (Niikura, US Patent Application No: 16/484,061, published as US 2019/0359691).
Antibody diversity: Niikura, *US Patent Application No: 16/484,061, published as US 2019/0359691) discloses a process for promoting diversificaiton of amino acid sequences of variable regions of an antibody generated by an avian B cell poluation that includes suppressing PI3Kalpha activity of an avian b cell population. In one embodiment, the PI3kalpha-specific inhibitor is PI3Kalpha inhibitor 2 or A66.
Antibody Class Switching: PI3 Kinase (phosphoinositide 3-kinase, PI3k) has been known as a factor functioning upstream of AID. As a result of studies using a PI3K inhibitor in mouse B cells, it has been demonstrated that when p110episolon signaling is suppressed, the expression of AID is increased and class switch recombination is promoted. (Niikura, US Patent Application No: 16/484,061, published as US 2019/0359691).
Role in Leukocyte chemotaxis: PI3Ks are known to play a pivotal role in the ability of leukocytes to undergo chemotaxis as the lipid products they generate, including but not limited to phosphatidylinositol (3,4,5)-trisphosphate (PI3), are ciritical for promoting asymmetric F-actin synthesis, and thus luekocyte cell polization. The function of class I PI3Ks, however, is not limited to directed migration, in that they are also required for phagocytosis and generation of oxygen radicals in response to chemoattractants. The ability of class I PI3Ks to regulated these processes in leukocytes relies on PIP3 mediated recruitment of two lipd-binding protein inases, phosphatidylinositol-dependent kinase 1 (PDK1) and protein kinase B/Akt, both of which can interact with this PI-derivative via their pleckstrin homology domains. Association of these kinases with PIP3 at the plasma membrane brings them into close proximity, facilitating the phosphorylation and activaiton of Akt by PDK1. These proteins are, in turn, responsible for many of the donstream signaling events associated with PI3K activity.
Role in neutrophil cell migration: Evidence supporting the class I PI3Ks involvement in neutrophil cell migration is found in the ability of non-selective class I PI3k inhibitors to mitigate neutrophil chemotaxis.
Effect on TLR3 Signalling: It is known that PI3 kinase activation is required for TLR3-induced IRF3 activation and subsequent IFN-beta gene induction.
Inhibitors of PI3 Kinase:
LY294002 is a pharmacological inibitor of PI#k.