Cheng A M, Negishi I, Anderson S J, Chan A C, Bolen J, Loh D Y, Pawson T
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada.
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9797-801. doi: 10.1073/pnas.94.18.9797.
An early stage in thymocyte development, after rearrangement of the beta chain genes of the T cell receptor (TCR), involves expression of the pre-TCR complex and accompanying differentiation of CD4(-)CD8(-) double negative (DN) cells to CD4(+)CD8(+) double positive (DP) cells. The ZAP-70 and Syk tyrosine kinases each contain two N-terminal SH2 domains that bind phosphorylated motifs in antigen receptor subunits and are implicated in pre-T receptor signaling. However, mice deficient in either ZAP-70 or Syk have no defect in the formation of DP thymocytes. Here we show that, in mice lacking both Syk and ZAP-70, DN thymocytes undergo beta chain gene rearrangement but fail to initiate clonal expansion and are incapable of differentiating into DP cells after expression of the pre-TCR. These data suggest that the ZAP-70 and Syk tyrosine kinases have crucial but overlapping functions in signaling from the pre-TCR and hence in early thymocyte development.
在胸腺细胞发育的早期阶段，T细胞受体（TCR）的β链基因重排后，会涉及前TCR复合物的表达以及CD4(-)CD8(-)双阴性（DN）细胞向CD4(+)CD8(+)双阳性（DP）细胞的伴随分化。ZAP-70和Syk酪氨酸激酶各自含有两个N端SH2结构域，它们可结合抗原受体亚基中的磷酸化基序，并参与前T受体信号传导。然而，缺乏ZAP-70或Syk的小鼠在DP胸腺细胞的形成上没有缺陷。在此我们表明，在同时缺乏Syk和ZAP-70的小鼠中，DN胸腺细胞会发生β链基因重排，但无法启动克隆扩增，并且在前TCR表达后无法分化为DP细胞。这些数据表明，ZAP-70和Syk酪氨酸激酶在前TCR信号传导中具有关键但重叠的功能，因此在早期胸腺细胞发育中也具有关键但重叠的功能。
