The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62(dok) (Dok1) and activates NF-kappa B

The X-linked lymphoproliferative syndrome (XLP) is a genetic disorder in wh ich affected males have a morbid or fatal response to Epstein-Barr virus in fection. The XLP deficiency has been mapped to a gene encoding a 128-residu e protein, SH2D1A, which is comprised principally of a src homology 2 (SH2) domain. We now report that SH2D1A associates with Dok1. a protein that int eracts with Ras-CAP, Csk, and Nck, An SH2D1A SH2 domain mutant that has bee n identified in XLP does not associate with Dok1, in accord with the hypoth esis that this interaction is linked to XLP, The association of SH2D1A with Dok1 also depends on phosphorylation of Dok1 Y-449 in the sequence ALYSQVQ K. Further, overexpression of SH2D1A is found to activate NF-kappa B in 293 T cells. NF-kappa B activation by SH2D1A does not depend on the wild-type S H2 domain and is inhibited by a dominant-negative I kappa B kinase beta, Th us, SH2D1A can affect multiple intracellular signaling pathways that are po tentially important in the normal effective host response to Epstein-Barr v irus infection.