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.
Perez
Omar D
OD
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Kinoshita
Shigemi
S
Hitoshi
Yasumichi
Y
Payan
Donald G
DG
Kitamura
Toshio
T
Nolan
Garry P
GP
Lorens
James B
JB
D064413:3-Phosphoinositide-Dependent Protein Kinases; D016475:3T3 Cells; D000185:Actinin / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002470:Cell Survival; D003598:Cytoskeletal Proteins; D004789:Enzyme Activation; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099149:Ezrin
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000185:Actinin; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D000099149:Ezrin; C065289:ICAM2 protein, human