Cellular Function of Phosphoinositide 3-Kinases: Implications for Development, Immunity, Homeostasis, and Cancer

Abstract

The phosphoinositide 3-kinase (PI3K) family of enzymes is recruited upon growth factor receptor activation and produces 3' phosphoinositide lipids. The lipid products of PI3K act as second messengers by binding to and activating diverse cellular target proteins. These events constitute the start of a complex signaling cascade, which ultimately results in the mediation of cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. Therefore, PI3Ks play a central role in many cellular functions. The factors that determine which cellular function is mediated are complex and may be partly attributed to the diversity that exists at each level of the PI3K signaling cascade, such as the type of stimulus, the isoform of PI3K, or the nature of the second messenger lipids. Numerous studies have helped to elucidate some of the key factors that determine cell fate in the context of PI3K signaling. For example, the past two years has seen the publication of many transgenic and knockout mouse studies where either PI3K or its signaling components are deregulated. These models have helped to build a picture of the role of PI3K in physiology and indeed there have been a number of surprises. This review uses such models as a framework to build a profile of PI3K function within both the cell and the organism and focuses, in particular, on the role of PI3K in cell regulation, immunity, and development. The evidence for the role of deregulated PI3K signaling in diseases such as cancer and diabetes is reviewed.

Cell biology of embryonic migration

“…In addition, knockouts of some of the regulatory molecules directly involved in the regulation of the mechanistic components of cell migration have been described and are listed separately in the table. Knockouts of other regulatory molecules, such as PI3K and PTEN, have also been characterized (Di Cristofano et al, 1998;Jou et al, 2002;Katso et al, 2001;Stambolic et al, 2000;Suzuki et al, 2003), but are too general to be implicated directly in migration and have therefore been removed from our list.…”

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

“…Molecular immunology distinct cellular functions [34][35][36]. The most wellcharacterized class, I A PI3K, comprises heterodimers consisting of an 85-kDa regulatory subunit and a 110-kDa catalytic subunit.…”

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

“…(8,12) The phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3 0 -hydroxyl group on the inositol ring of phosphatidylinositol. (13)(14)(15) Based on the sequence similarity, composition of the subunits, and substrate specificity, the PI3Ks are divided into three classes: class I, II, and III PI3Ks. Class I PI3K is activated in response to a variety of extracellular stimuli and generates the second messenger phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P 3 ) as a result of the phosphorylation of PI-4,5-P 2 , whereas class II and III PI3Ks are constitutively activated and generate PI-3-P. Class I PI3K is a heterodimer of the regulatory and catalytic subunits, and the regulatory subunit is required for the stability as well as kinase activity of the catalytic subunit.…”