Activation of the PKB/AKT pathway by ICAM-2.

We identified intracellular adhesion molecule-2 (ICAM-2) in a genetic screen as an activator of the PI3K/AKT pathway leading to inhibition of apoptosis. ICAM-2 induced tyrosine phosphorylation of ezrin and PI3K kinase membrane translocation, resulting in phosphatidylinositol 3,4,5 production, PDK-1 and AKT activation, and subsequent phosphorylation of AKT targets BAD, GSK3, and FKHR. ICAM-2 clustering protected primary human CD19+ cells from TNFalpha- and Fas-mediated apoptosis as determined by single-cell analysis. ICAM-2 engagement by CD19+ cells of its natural receptor, LFA-1, on CD4+ naive cells specifically induced AKT activity in the absence of an MHC-peptide interaction. These results attribute a novel signaling function to ICAM-2 that might suggest mechanisms by which ICAM-2 signals intracellular communication at various immunological synapses.

[1]  P. Kovanen,et al.  ICAM-2 redistributed by ezrin as a target for killer cells , 1996, Nature.

[2]  A. Mammoto,et al.  Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl , 1998, Oncogene.

[3]  T. Springer,et al.  Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1 , 1991, The Journal of experimental medicine.

[4]  C. Gahmberg,et al.  Binding of the Cytoplasmic Domain of Intercellular Adhesion Molecule-2 (ICAM-2) to α-Actinin* , 1996, The Journal of Biological Chemistry.

[5]  J V Giorgi,et al.  Quantitation of CD38 expression using QuantiBRITE beads. , 1998, Cytometry.

[6]  A. Gautreau,et al.  Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N. Takahashi,et al.  Ezrin/Radixin/Moesin (ERM) Proteins Bind to a Positively Charged Amino Acid Cluster in the Juxta-Membrane Cytoplasmic Domain of CD44, CD43, and ICAM-2 , 1998, The Journal of cell biology.

[8]  S. Tsukita,et al.  ERM proteins: head-to-tail regulation of actin-plasma membrane interaction. , 1997, Trends in biochemical sciences.

[9]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[10]  M. Raff,et al.  Social controls on cell survival and cell death , 1992, Nature.

[11]  A. Mes-Masson,et al.  Allelotyping defines minimal imbalance at chromosomal region 17q25 in non-serous epithelial ovarian cancers , 2000, Oncogene.

[12]  L. Mcphail,et al.  Protein kinase C (PKC) isoforms translocate to Triton-insoluble fractions in stimulated human neutrophils: correlation of conventional PKC with activation of NADPH oxidase. , 1999, Journal of immunology.

[13]  M. Raff,et al.  Programmed cell death and Bcl-2 protection in very low oxygen , 1995, Nature.

[14]  J. Downward.  Mechanisms and consequences of activation of protein kinase B/Akt. , 1998, Current opinion in cell biology.

[15]  A. Bretscher,et al.  ERM-Merlin and EBP50 protein families in plasma membrane organization and function. , 2000, Annual review of cell and developmental biology.

[16]  C. Gahmberg,et al.  Expression of endothelial adhesion molecules in vivo. Increased endothelial ICAM-2 expression in lymphoid malignancies. , 1992, The American journal of pathology.

[17]  G. Nolan,et al.  Efficient screening of retroviral cDNA expression libraries. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[19]  Garry P. Nolan,et al.  Simultaneous measurement of multiple active kinase states using polychromatic flow cytometry , 2002, Nature Biotechnology.

[20]  James Monypenny,et al.  Ezrin is a downstream effector of trafficking PKC–integrin complexes involved in the control of cell motility , 2001, The EMBO journal.

[21]  S. Molica,et al.  Intercellular adhesion molecules (ICAMs) 2 and 3 are frequently expressed in B cell chronic lymphocytic leukemia. , 1996, Leukemia.

[22]  John Calvin Reed,et al.  Anchorage dependence, integrins, and apoptosis , 1994, Cell.

[23]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[24]  E Ruoslahti,et al.  Integrins and anoikis. , 1997, Current opinion in cell biology.

[25]  J. Trowsdale,et al.  The human ICAM2 gene maps to 17q23-25. , 1991, Genomics.

[26]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[27]  B. Engelhardt,et al.  Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness. , 1999, Immunity.

[28]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[29]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[30]  K. Fujii,et al.  CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells1 , 2001, The Journal of Immunology.

[31]  Michael Loran Dustin,et al.  Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1 , 1989, Nature.

[32]  Simmons Dl.  The role of ICAM expression in immunity and disease , 1995 .

[33]  C. Figdor,et al.  Avidity regulation of integrins: the driving force in leukocyte adhesion. , 2000, Current opinion in cell biology.

[34]  T. Springer,et al.  A functional integrin ligand on the surface of platelets: intercellular adhesion molecule-2. , 1994, The Journal of clinical investigation.