Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in TH2 cytokine regulation
Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in TH2 cytokine regulation
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DOI：
10.1016/j.immuni.2004.10.005
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发表时间：
2004-11-01
期刊：
影响因子：
32.4
通讯作者：
Veillette, A
中科院分区：
文献类型：
--
作者：
Davidson, D;Shi, XC;Veillette, A
SAP是在X连锁淋巴组织增生性疾病中突变的衔接子。它在T辅助细胞2（T（H）2）细胞因子的产生中起关键作用。该功能被认为反映了SAP与SLAM家族受体结合的能力，并通过SAP介导的Src相关激酶FynT的募集使这些受体能够进行酪氨酸磷酸化信号传导。在这里，我们通过遗传手段解决了SAP-FynT相互作用在正常T细胞功能中的重要性。通过创建其中SAP的FynT结合位点在生殖系中失活的小鼠（sap（R78 A）小鼠），并通过分析缺乏SAP、FynT或SLAM的小鼠，获得了SAP-FynT级联对于体外和体内正常T（H）2功能确实至关重要的证据。这些数据表明，SAP是T（H）2细胞因子调节所必需的，主要是由于其募集FynT的能力。他们还确定了FynT在SAP依赖性T（H）2细胞因子调节中的先前未被认识的作用。
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.