Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation.
SAP is an adaptor mutated in X-linked lymphoproliferative disease. It plays a critical role in T helper 2 (T(H)2) cytokine production. This function was suggested to reflect the capacity of SAP to associate with SLAM family receptors and enable tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase FynT. Here, we addressed by genetic means the importance of the SAP-FynT interaction in normal T cell functions. By creating a mouse in which the FynT binding site of SAP was inactivated in the germ line (sap(R78A) mouse) and by analyzing mice lacking SAP, FynT or SLAM, evidence was obtained that the SAP-FynT cascade is indeed crucial for normal T(H)2 functions in vitro and in vivo. These data imply that SAP is necessary for T(H)2 cytokine regulation primarily as a result of its capacity to recruit FynT. They also establish a previously unappreciated role for FynT in SAP-dependent T(H)2 cytokine regulation.
Davidson
Dominique
D
Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montréal, Québec H2W 1R7, Canada.
Shi
Xiaochu
X
Zhang
Shaohua
S
Wang
Hao
H
Nemer
Mona
M
Ono
Nobuyuki
N
Ohno
Shinji
S
Yanagi
Yusuke
Y
Veillette
André
A
D000818:Animals; D015703:Antigens, CD; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000235:genetics; D050990:GATA3 Transcription Factor; D006023:Glycoproteins / Q000502:physiology; D007073:Immunoglobulin E / Q000096:biosynthesis; D007136:Immunoglobulins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011956:Receptors, Cell Surface; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D015534:Trans-Activators; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D007073:Immunoglobulin E; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn