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Blood, 1 July 2005, Vol. 106, No. 1, pp. 4-5. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Abrams, C. S. Search for Related Content PubMed Articles by Abrams, C. S. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Comment on Munugalavadla et al, page 103, and Puri et al, page 150 A little grease helps the cell to stick Charles S. Abrams UNIVERSITY OF PENNSYLVANIA Cell adhesion and migration are both regulated by the rapid synthesis of lipids in the plasma membrane by phosphatidylinositol 3-kinase (PI3K). Phosphatidylinositol 3-kinases (PI3Ks) are a diverse family of enzymes that phosphorylate the D-3 position of the inositol ring of phosphatidylinositol to produce phosphatidylinositol 3-phosphate (PI3-P), phosphatidylinositol 3,4-bisphosphates (PI3,4-P2), and phosphatidylinositol 3,4,5-triphosphates (PI3,4,5-P3 or PIP3). The 4 human isoforms of PI3K that generate PIP3 are classified by their catalytic subunit: p110, p110, p110, and p110. The p110, p110, and p110 isoforms (PI3K, PI3K, and PI3K) associate with the regulatory subunit p85, and are tightly linked to signaling by growth factor, immunoglobulin, and cytokine receptors. The p110 isoform (PI3K) is stimulated by G-protein heterodimers (G) and associates with p101, a regulatory subunit that has no similarity to p85. Although it was originally described in myeloid cells, PI3K has been found in other blood cells as well as the endothelium.1,2 Cells undergoing chemotaxis develop a polarity with a lamellipodia in the front of the cell that is rich in F-actin and a uropod in the rear of the cell that also contains actin-binding proteins such as moesin, intercellular adhesion molecule 3 (ICAM-3), and myosin. Chemotaxis occurs by the alignment of this polarity along a gradient of chemoattractant. Studies in Dictyostelium and murine hematopoietic cells have shown that PI3K is critical for chemotaxis, but the particular isoform required appears to depend on the cell type. For example, neutrophil chemotaxis requires PI3K and PI3K3,4 but monocyte chemotaxis requires PI3K and PI3K.5,6 In these examples, a chemoattractant stimulates the transient accumulation of PIP3, and therefore PIP3-binding proteins, at the plasma membrane along the leading edge of the cell. Phosphatase and tensin homolog (PTEN), a phospholipid phosphatase localized at the rear of the cell, ensures the relative dearth of PIP3 and its binding partners at the trailing edge (see figure). View larger version (26K): [in this window] [in a new window]   Although both spreading and migration involve actin polymerization and protrusion, cell locomotion is complex and requires cell polarity, contraction, and deadhesion, none of which are needed for spreading. PI3K at the leading edge of a cell is important for generating PIP3. Localized PIP3 binds specific actin regulatory proteins and leads to F-actin assembly. PTEN is an inositol phosphatase localized at the trailing edge of the migrating cell that dephosphorylates PIP3 into PIP2.   Like cell migration, adhesion also involves lamellipodia formation and PI3K-induced actin polymerization. But cell migration is more complex because it requires cell polarity, contraction, and de-adhesion, none of which are needed for simple adhesion. For example, nonlocalized activation of Rac leads a nonpolarized increase in F-actin and adhesion that retards cell migration. In this issue of Blood, 2 articles address the relationship between specific PI3K isoforms and the migration and adhesion of hematopoietic cells. First, Munugalavadla and colleagues rigorously characterized the defects in monocytes lacking the dominant isoform of p85 (and hence the majority of PI3K, PI3K, and PI3K activity). Using several independent assays of directional cell migration, they found marked defects in both cell adhesion and migration. Second, Puri and colleagues analyzed the role of PI3K in neutrophil migration along inflamed blood vessel walls. Given the known role of PI3K in cell adhesion, they found the expected result that neutrophil adhesion to the endothelium was markedly impaired in PI3K and PI3K knockout mice. Remarkably, they found that wild-type neutrophils were also impaired in their ability to adhere to PI3K knockout endothelial cells. This demonstrates the importance of a PI3K-dependent signaling cascade within endothelial cells, that is, cells required for their adhesion to neutrophils. Puri and colleagues speculate that endothelial cell PI3K is required for an endothelial cell adhesion receptor, E-selectin, to tether neutrophils. Although at this point, other possible explanations still exist. In addition to chemotaxis and adhesion, PI3Ks are involved in diverse cellular events, including the prevention of apoptosis, regulation of glucose metabolism, and cell proliferation. Lessons from pharmacologic inhibitors, knockout mice, and single-cell microscopy studies have advanced our knowledge of these processes considerably over the past few years. The challenge will be to inhibit specific PI3K isoforms in discreet regions of cells to target migration without affecting other PI3K-dependent processes. References Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell. 1994;77: 83-93.[CrossRef][Medline] [Order article via Infotrieve] Cieslik K, Abrams CS, Wu KK. Up-regulation of endothelial nitric-oxide synthase promoter by the phosphatidylinositol 3-kinase gamma/Janus kinase 2/MEK-1-dependent pathway. J Biol Chem. 2001;276: 1211-1219.[Abstract/Free Full Text] Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D. Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science. 2000;287: 1046-1049.[Abstract/Free Full Text] Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE. Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J Immunol. 2003;170: 2647-2654.[Abstract/Free Full Text] Vanhaesebroeck B, Jones GE, Allen WE, et al. Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol. 1999;1: 69-71.[CrossRef][Medline] [Order article via Infotrieve] Jones GE, Prigmore E, Calvez R, et al. Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1. Exp Cell Res. 2003;290: 120-131.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: p85 subunit of class IA PI-3 kinase is crucial for macrophage growth and migration Veerendra Munugalavadla, Jovencio Borneo, David A. Ingram, and Reuben Kapur Blood 2005 106: 103-109. [Abstract] [Full Text] [PDF] The role of endothelial PI3K activity in neutrophil trafficking Kamal D. Puri, Teresa A. Doggett, Ching-Yu Huang, Jason Douangpanya, Joel S. Hayflick, Martin Turner, Josef Penninger, and Thomas G. Diacovo Blood 2005 106: 150-157. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Abrams, C. S. Search for Related Content PubMed Articles by Abrams, C. S. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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