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Association of the X-linked Lymphoproliferative Disease Gene Product SAP/SH2D1A with 2B4, a Natural Killer Cell-activating Molecule, Is Dependent on Phosphoinositide 3-Kinase
- Source :
- Journal of Biological Chemistry. 277:13331-13337
- Publication Year :
- 2002
- Publisher :
- Elsevier BV, 2002.
-
Abstract
- Natural killer (NK) cells express an activating receptor, 2B4, that enhances cellular cytotoxicity. Upon NK cell activation by ligation of 2B4, the intracellular domain of 2B4 associates with the X-linked lymphoproliferative disease (XLP) gene product, signaling lymphocytic activation molecule-associated protein/SH2D1A (SAP/SH2D1A). Defective intracellular association of 2B4 with mutated SAP/SH2D1A is likely to underlie the defects in cytotoxicity observed in NK cells from patients with XLP. We report here a role for phosphoinositide 3-kinase (PI3K) in the recruitment and association of SAP/SH2D1A to 2B4 in human NK cells. The activation of normal NK cells by ligation of 2B4 leads to the phosphorylation of 2B4, recruitment of SAP/SH2D1A, and association of the p85 regulatory subunit of PI3K. The inhibition of PI3K enzymatic activity with either wortmannin or LY294002 prior to 2B4 ligation does not alter the association of 2B4 with the p85 subunit but prevents the recruitment of SAP/SH2D1A to 2B4. In addition, PI3K inhibitors significantly diminish the cytotoxic function of primary NK cells. This observed inhibition of cytotoxicity, present in normal NK cells, was less apparent or absent in NK cells derived from a patient with XLP. These data indicate that the cytotoxicity of activated NK cells is mediated by the association of 2B4 and SAP/SH2D1A, and that this association is dependent upon the activity of PI3K.
- Subjects :
- X Chromosome
Genetic Linkage
Morpholines
Molecular Sequence Data
Biology
Lymphocyte Activation
Biochemistry
Natural killer cell
Wortmannin
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Interleukin 21
Antigens, CD
Signaling Lymphocytic Activation Molecule Family
medicine
Humans
Cytotoxic T cell
LY294002
Amino Acid Sequence
Signaling Lymphocytic Activation Molecule Associated Protein
Enzyme Inhibitors
Phosphorylation
Receptors, Immunologic
Molecular Biology
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Membrane Glycoproteins
Phosphoinositide 3-kinase
Intracellular Signaling Peptides and Proteins
Cell Biology
Lymphoproliferative Disorders
Cell biology
Androstadienes
Killer Cells, Natural
medicine.anatomical_structure
chemistry
Chromones
Mutation
Interleukin 12
biology.protein
Carrier Proteins
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 277
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....405b77d300a54553457ef9a298f62e51