TY - JOUR
T1 - The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-κB
AU - Sylla, Bakary S.
AU - Murphy, Kerry
AU - Cahir-McFarland, Ellen
AU - Lane, William S.
AU - Mosialos, George
AU - Kieff, Elliott
PY - 2000/6/20
Y1 - 2000/6/20
N2 - 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 Y449 in the sequence ALYSQVQK. Further, overexpression of SH2D1A is found to activate NF-κB in 293T cells. NF-κB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IκB kinase β. Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus infection.
AB - 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 Y449 in the sequence ALYSQVQK. Further, overexpression of SH2D1A is found to activate NF-κB in 293T cells. NF-κB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IκB kinase β. Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus infection.
KW - Epstein-Barr virus
KW - Genetic disease
UR - http://www.scopus.com/inward/record.url?scp=0034691123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034691123&partnerID=8YFLogxK
U2 - 10.1073/pnas.130193097
DO - 10.1073/pnas.130193097
M3 - Article
C2 - 10852966
AN - SCOPUS:0034691123
SN - 0027-8424
VL - 97
SP - 7470
EP - 7475
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -