Special Perspectives

PI3Kγ Is a Key Regulator of Inflammatory Responses and Cardiovascular Homeostasis

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Science  05 Oct 2007:
Vol. 318, Issue 5847, pp. 64-66
DOI: 10.1126/science.1145420


Class I phosphoinositide 3-kinase (PI3K) signaling pathways regulate several important cellular functions, including cellular growth, division, survival, and movement. Class IB PI3K (also known as PI3Kγ) links heterotrimeric GTP-binding protein–coupled receptors to these pathways. Activation of class IB PI3K results in the rapid synthesis of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] and its dephosphorylation product PtdIns(3,4)P2 in the plasma membrane. These two lipid messengers bind to pleckstrin homology domain–containing effectors that regulate a complex signaling web downstream of receptor activation. Characteristic features of this pathway are the regulation of protein kinases and the regulation of small guanosine triphosphatases that control cellular movement, adhesion, contraction, and secretion. Most of the ligands that activate class IB PI3K are involved in coordinating the body's response to injury and infection, and recent studies suggest that small molecule inhibitors of this enzyme may represent a novel class of anti-inflammatory therapeutic agents.

Class I PI3Ks are well-established signal transduction enzymes that drive extensive signaling networks downstream of cell surface receptor activation (1). Most of the interest in these enzymes has focused on the important roles of class IA PI3Ks (PI3Kα, β, and δ) in coordinating cell growth, division, and survival in response to activation of protein tyrosine kinase–coupled growth factor receptors. In contrast, class IB PI3K (PI3Kγ) allows fastacting, heterotrimeric G protein–coupled receptors to access PI3K signaling networks. Most of the ligands that have been established to activate PI3Kγ are involved in the regulation of multiple cell types in the immune system and vascular lining, and mice lacking the catalytic subunit of PI3Kγ are generally healthy but remarkably resistant to the development of several inflammatory pathologies in mouse models of human inflammatory disease (2, 3).

PI3Kγ was originally characterized as a heterodimer of p101 regulatory and p110γ catalytic subunits (4, 5). A homolog of p101, called p84 or p87PIKAP, has recently been discovered that also forms dimers with p110γ, but the relative tissue expression and relevance of p101 versus p84 to the activation of PI3Kγ in different cellular contexts has yet to be established (6, 7). PI3Kγ is a lipid kinase that catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] in the inner leaflet of the plasma membrane. This lipid kinase activity is stimulated by the combined actions of p101- or p84-dependent interaction with Gβγ subunits and p110γ-dependent interaction with guanosine triphosphate (GTP)–bound Ras (8). Gβγ subunits are liberated during the direct interaction of receptors with the G, family of heterotrimeric GTP-binding proteins, but the origin of GTP-bound Ras in this pathway has yet to be established.

PtdIns(3,4,5)P3, and its dephosphorylation product PtdIns(3,4)P2, are signaling lipids whose increases in concentration coordinate the plasma membrane localization and regulation of several direct protein effectors. The magnitude and timing of these lipid signals is also controlled by phosphatases that remove the 5-[such as Src homology 2 (SH2) domain–containing inositol polyphosphate 5-phosphatase (SHIP) and other inositol polyphosphate 5-phosphatases], 3-(such as PTEN), and 4-(such as inositol polyphosphate 4-phosphatases) monoesterified phosphates from these lipids. As with other phosphoinositides [for example, PtdIns3P, PtdIns4P, PtdIns(3,5)P2, and PtdIns(4,5)P2], PtdIns(3,4,5)P3 and PtdIns(3,4)P2 recognize their protein effectors by binding to conserved families of small, lipid binding domains. PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are thought to bind predominantly to a subfamily of pleckstrin homology (PH) domains, which bind the headgroup of either or both of these lipids with high affinity and specificity (1). A characteristic feature of PI3K signaling pathways is the large number of direct, PH domain–containing effectors and the complex signaling networks in which they are involved, usually in partnership with other signaling pathways that are activated in parallel (Fig. 1). The relative abundance of these effectors and their targets define the nature of the regulatory experience delivered in a particular cellular context; however, the activation of the serine/threonine kinase PKB (protein kinase B, also known as Akt) appears to be a universal response to activation of this pathway and plays a key role in regulating metabolic, secretory, and transcriptional responses [see the canonical PI3K class IB pathway in Science's STKE database (9)].

Fig. 1.

This schematic diagram places the class IB signaling pathway into perspective, with respect to the other signaling pathways that usually operate in parallel to deliver physiological regulation in any particular context of cellular regulation. Some examples of the various categories of signaling elements are shown to illustrate different levels of signaling organization, but the lists are not meant to be exhaustive. Additional abbreviations are as follows: ECM, extracellular matrix; FcRs, Fc receptors; TLRs, Toll-like receptors; GPCRs, G protein–coupled receptors; GEFs, guanine nucleotide exchange factors; GAP, GTPase-activating protein; and NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.

PI3Kγ is activated by several chemokines [for example, interleukin-8, macrophage inflammatory protein (MIP)–1α, MIP-2, MCP-1, Gro-α, and RANTES], pro-inflammatory lipids (for example, PAF and LTB4), bacterial products [for example, N-formyl-Met-Leu-Phe (fMLP)], and other vaso-active stimuli [for example, C5a, adenosine diphosphate (ADP), and angiotensin II], acting predominantly through Gi-coupled receptors (2, 3). Thus, this pathway is involved in the regulation of several cell types that are classically considered to be part of the innate and adaptive immune system (neutrophils, macrophages, monocytes, endothelial cells, mast cells, dendritic cells, and T cells) and also cell types additionally involved in the regulation of blood pressure (smooth muscle cells) and blood clotting (platelets). Most of these cell act together in coordinated responses to injury and infection that involve multiple ligands, receptors, and intracellular signaling cascades. Where sufficient detail is known concerning the regulation of a particular cell type, it invariably seems that activation of PI3Kγ by Gi-coupled receptors acts cooperatively with ligands working through other receptor types. Often these other receptors transduce their signals through protein tyrosine kinases, which in turn activate class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) (1). Further, sustained activation of Gi-coupled receptors often stimulates Src family protein tyrosine kinases and subsequently activates class IA PI3Ks in parallel to PI3Kγ. Thus, in many contexts of cellular activation, multiple class I PI3Ks are involved. Because a major class IA PI3K in the hematopoietic system is PI3Kδ, PI3Kγ and PI3Kδ are often found working together to deliver physiological regulation of a particular response. Despite the apparent opportunity for redundancy that these complex signaling systems represent, work with p110γ knockout (KO) mice indicates that PI3Kγ plays a nonredundant role in several important physiological responses (2, 3), probably because of its partial contribution to so many of the relevant cell-activation pathways.

PI3Kγ was discovered in neutrophils, and initially its expression was thought to be restricted to cells of the hematopoietic lineage; hence, most of our knowledge of this enzyme comes from the study of neutrophils and related cell types [see the specific PI3K class IB pathway in Science's STKE database (10)]. Activation of neutrophil PI3Kγ by chemoattractants present on the surface of inflamed endothelium regulates the efficiency with which these cells are captured and exit the vasculature. Activation of PI3Kγ also contributes to the efficiency with which neutrophils chemotax toward higher concentrations of chemoattractants released at sites of infection and inflammation and also to the efficiency with which they secrete proteases, reactive oxygen species (ROS), and other antimicrobial products at their final destination (usually in response to high concentrations of end-point chemoattractants and priming cytokines). The cooperation between chemoattractants and cytokines in the delivery of maximal ROS production appears to involve the sequential activation of PI3Kγ and PI3Kδ. The molecular details of how PtdIns(3,4,5)P3 and PtdIns(3,4)P2 coordinate the regulation of these neutrophil responses are still incompletely understood, but it is clear that there is a central role for the regulation of small gunosine triphosphatases (GTPases) of the Rac and Rho family and the Arf family and that this is likely to be a general feature of this pathway in different cell types. There also appears to be a small role for PI3Kγ in the development of the inflamed endothelium itself. The net result of all of these effects probably explains why several laboratories have reported a substantial reduction in the speed and sometimes extent to which neutrophils arrive at sites of inflammation in p110γ KO mice (2).

PI3Kγ also plays an important role in other immune cells and their functions, for example, in the chemotaxis of cells in the monocyte or macrophage lineage to sites of inflammation, in the homing of dendritic cells to lymph nodes, and in the development and activation of T lymphocytes (this last is a partially redundant role with PI3Kδ) (2, 3). PI3Kγ also contributes to the activation of mast cell secretion by adenosine, in concert with immunoglobulin E (IgE)–dependent activation of PI3Kδ, and to the activation of platelet aggregation by ADP, in concert with PI3Kβ (2, 3). It seems likely that PI3Kγ is involved in purinergic stimulation of autocrine and paracrine regulatory loops in other cell typesaswell.

Although PI3Kγ was initially thought to be restricted to cells of the hematopoietic lineage, it is now clear that this isoform also plays key roles in additional cell types. There is good evidence that PI3Kγ participates in angiotensin II regulation of smooth muscle contraction (11), and there is a fascinating story emerging on the role of PI3Kγ in the regulation of myocyte contractility (12). In particular, a comparison between the differential effects of p110γ deletion and a p110γ kinase–dead knockin mutation suggests that p110γ contributes a nonlipid kinase or scaffolding function to the reduction of cyclic adenosine monophosphate (cAMP) concentration in myocytes, delivering decreased contractile force in response to β-adrenergic stimulation. The mechanism for this effect may involve direct binding of PI3Kγ to a cAMP phosphodiesterase (PDE3B).

Because PI3Kγ is involved in the mechanisms that direct several types of immune cells to sites of inflammation in the joints, lungs, and other organs, several laboratories have investigated the susceptibility of p110γ KO mice to various models of inflammatory disease, particularly those with an autoimmune component. Descriptions of PI3Kγ involvement in the regulation of blood vessel contraction, clot formation, and the heart are also starting to prompt the analysis of these mice in models of cardiovascular disease (13). This work is driven by the knowledge that the adenosine triphosphate–binding site of the catalytic subunit of PI3Ks is a druggable target, with PI3K isoform-selective inhibitors in development in several pharmaceutical companies (2). The first PI3Kγ-selective inhibitors are now starting to appear, with efficacy so far in the treatment of mouse models of rheumatoid arthritis (14) and systemic lupus (15).

There is clearly still much to be discovered about the regulation of PI3Kγ individual receptors, the relative contributions of Gβγ subunits and Ras, the importance of p101 versus p84, and also the potential new scaffolding functions for both regulatory and catalytic subunits. There is also still more to learn about how the lipid products of PI3Kγ regulate complex cellular responses in different cell types. Perhaps of greatest general interest, however, is just how effective the first p110γ-specific inhibitors will prove to be in clinical trials of human inflammatory disease.

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