The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B.
The X-linked lymphoproliferative syndrome (XLP) is a genetic disorder in which affected males have a morbid or fatal response to Epstein-Barr virus infection. The XLP deficiency has been mapped to a gene encoding a 128-residue protein, SH2D1A, which is comprised principally of a Src homology 2 (SH2) domain. We now report that SH2D1A associates with Dok1, a protein that interacts with Ras-GAP, Csk, and Nck. An SH2D1A SH2 domain mutant that has been identified in XLP does not associate with Dok1, in accord with the hypothesis that this interaction is linked to XLP. The association of SH2D1A with Dok1 also depends on phosphorylation of Dok1 Y(449) in the sequence ALYSQVQK. Further, overexpression of SH2D1A is found to activate NF-kappaB in 293T cells. NF-kappaB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IkappaB kinase beta. Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus infection.
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Departments of Medicine and Microbiology and Molecular Genetics, Brigham and Women's Hospital and Harvard University, 181 Longwood Avenue, Boston, MA 02115; and Microchemistry Facility, Harvard University, 16 Divinity Avenue, Cambridge, MA.
Murphy
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Cahir-McFarland
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Lane
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Mosialos
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Kieff
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D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D020031:Epstein-Barr Virus Infections / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013577:Syndrome; D014407:Tumor Cells, Cultured; D014960:X Chromosome
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C074561:GAP-associated protein p62; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein