Signaling by the phosphoinositide 3-kinase family in immune cells

Abstract

Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular.

Figure 1

a) Numbering of the carbons of the myo-inositol ring. b) Phosphatidyliositol and its 7 phosphorylated derivatives. The kinases and phosphatases shown are described in the text, except the PI4 and PI5 kinase that cooperate to generate PI(4,5)P2, the substrate of the class I PI3Ks.

Figure 2

A. List of the genes and protein products of the mammalian PI3K family. B. Phylogenetic tree of the 8 mammalian PI3K catalytic subunits. The tree was generated using ClustalW (http://www.ebi.ac.uk/Tools/phylogeny/clustalw2_phylogeny/) C. The domain structures of the class III, II and I PI3Ks are represented by Vps34, CIIα and p110α, respectively. The domain structure of p85α is also shown. Not shown are class IB regulatory subunits and the Vps34 regulatory subunits. The Illustrations were generated using Prosite (http://prosite.expacy.org/scanprosite).

Figure 3

Schematic illustrating the recruitment of class I PI3Ks to tyrosine kinase-linked receptors and GPCRs. P110β is illustrated as a coincidence detector for tyrosine kinase and GPCR signalling.

Figure 4

Diagram illustrating the circular network that connects PI3K signalling to MTOR activation. Regulatory subunits are not shown. How Vps34 contributes to amino acid –dependent mTOR activity is incompletely understood. PI3Ki indicates various PI3K inhibitors, some of which can also inhibit mTOR. TORins describes ATP-competitive mTOR inhibitors. Rapamycin blocks mTORC1 specifically via its association with FKBP12 (not shown).

Figure 5