Immunology Letters 138 (2011) 15–18 Contents lists available at ScienceDirect Immunology Letters journal homepage: www.elsevier.com/locate/immlet Review Sat-Nav for T cells: Role of PI3K isoforms and lipid phosphatases in migration of T lymphocytes Stephen G. Ward a,∗ , John Westwick b , Stephanie Harris a a Department Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK b Novartis Institute for Biomedical Research, Wimblehurst Road Horsham, W. Sussex RH12 5AB, UK article info Article history: Available online 17 February 2011 Keywords: PI3K Migration T lymphocytes Inhibitors abstract Phosphoinositide 3-kinase (PI3K)-dependent signaling has been placed at the heart of conserved bio- chemical mechanisms that facilitate cell migration of leukocytes in response to a range of chemoattractant stimuli. This review assesses the evidence for and against PI3K-dependent mechanisms of T lymphocyte migration and whether pharmacological targeting of PI3K isoforms is likely to offer potential benefit for T cell mediated pathologies. © 2011 Elsevier B.V. All rights reserved. Lymphocyte migration is co-ordinated by selectins, integrins and chemokine receptors, an array of signaling events and cytoskeleton reorganisation. Ordered lymphocyte migration is cru- cial to thymic development, entry of naïve T cells into secondary lymphoid organs (SLO), their subsequent activation and maturation into circulating memory and effector T cells, and ultimately their egress from the SLO and homing to peripheral tissues. Phospho- inositide 3-kinase (PI3K)-dependent signaling has been placed at the heart of the biochemical mechanisms that facilitate cell migra- tion including leukocyte movement in response to chemoattractant inflammatory mediators such as members of the chemokine family. More recently, PI3K has also been demonstrated to be a key regu- lator in novel mechanisms mediated by the T cell antigen receptor (TCR) and the costimulatory molecule CD28 that guide the access and retention of specific T cells into antigen-rich non-lymphoid tissue [1]. 1. PI3K-dependent signaling cascade PI3Ks are a family of critical intracellular enzymes that catalyse the addition of a phosphate molecule specifically to the 3-position of the inositol ring to generate the D3 phosphoinositides, which include PI(3,4,5)P 3 , PI(3,4)P 2 , PI3P and, via PIKfyve, PI(3,5)P 2 . PI3K initiates signaling pathways that regulate vesicular trafficking, Abbreviations: GEF, guanine nucleotide exchange factors; GPCR, G protein coupled receptor; KLF-2, Kruppel-like factor-2; PI(3,4,5)P3, phosphatidylinositol- 3,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; SLO, secondary lymphoid organ; TCR, T cell antigen receptor. ∗ Corresponding author. Tel.: +44 1 225 323641. E-mail address: S.G.Ward@bath.ac.uk (S.G. Ward). cell proliferation, differentiation, protein translation, cell survival, actin cytoskeletal rearrangements and cell migration. PI(3,4,5)P 3 is the principal product of PI3K activity after receptor stimulation and it recruits and localises signaling proteins that contain lipid- binding pleckstrin homology (PH) domains to the inner wall of the plasma membrane, leading to their activation. These downstream effectors include PDK-1 (3 ′ -phosphoinositide dependent kinase- 1), which phosphorylates and activates the AGC family of kinases, including protein kinase B/Akt. Other kinases such as Tec family kinases can also interact with PI(3,4,5)P 3 , as well as scaffolding proteins which enable assembly of macromolecular signaling com- plexes, Rho family and ADP-ribosylation factor exchange factors and GTPase activating proteins [2,3]. The class 1 PI3Ks are composed of a regulatory subunit and a tightly associated catalytic subunit. The class 1A enzymes are rep- resented by five regulatory subunits encoded by three genes: PIK3r1 encodes p85 and its alternative transcripts p55 and p50. PIK3r2 encodes p85 and PIK3r3 encodes p55· The three class 1 catalytic isoforms p110, p110 and p110 pair with one of these regula- tory subunits which are responsible for recruitment of the complex to the plasma membrane upon receptor ligation. Class 1A isoforms are activated downstream of many immune cell receptors includ- ing the TCR, BCR, costimulatory molecules and cytokine receptors that are phosphorylated by tyrosine kinases upon cognate stim- ulus. The class 1B catalytic isoform p110 pairs with either the regulatory subunits p84/p87 or p101 and is activated by G pro- tein  subunits and signals downstream of G protein coupled receptors (GPCRs). It is becoming increasingly apparent however, that some GPCRs including chemokine receptors activate class IA PI3Ks, most notably p110 [4]. Expression of p110 and PI3K is largely restricted to leukocytes and mice in which the genes encod- ing p110 or p110 have been either ablated or altered to encode 0165-2478/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2011.02.007