A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase.
A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase.
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DOI：
10.1084/jem.20021498
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发表时间：
2003-02-17
期刊：
影响因子：
--
通讯作者：
Langdon WY
中科院分区：
文献类型：
--
作者：
Thien CB;Scaife RM;Papadimitriou JM;Murphy MA;Bowtell DD;Langdon WY
Cbl的独特酪氨酸激酶结合（TKB）结构域靶向活化的蛋白酪氨酸激酶（PTK）上的磷酸化酪氨酸;这种靶向被认为是Cbl蛋白负调节PTK所必需的。在这里，c-Cbl TKB结构域中的功能丧失突变（G304 E），首先在秀丽隐杆线虫中鉴定，被引入小鼠，并研究其在胸腺细胞和T细胞中的作用。与c-Cabl敲除小鼠形成鲜明对比的是，我们没有发现TKB结构域突变小鼠胸腺细胞中ZAP-70 PTK活性增强的证据。这一发现与公认的c-Cbl介导的负调控机制相矛盾，该机制需要ZAP-70中磷酸酪氨酸292的TKB结构域靶向。然而，TKB结构域突变小鼠确实显示出与c-Cbl敲除小鼠的信号传导平行的增强的信号传导方面，但这些方面涉及Rac的组成性激活而不是增强的PTK活性。此外，CD 4 + CD 8+双阳性胸腺细胞中增强的信号传导似乎通过来自两种突变型c-Cbl小鼠品系的成熟胸腺细胞和外周T细胞上的CD 3的选择性下调来补偿。
The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs. Here, a loss-of-function mutation (G304E) in the c-Cbl TKB domain, first identified in Caenorhabditis elegans, was introduced into a mouse and its effects in thymocytes and T cells were studied. In marked contrast to the c-Cbl knockout mouse, we found no evidence of enhanced activity of the ZAP-70 PTK in thymocytes from the TKB domain mutant mouse. This finding contradicts the accepted mechanism of c-Cbl–mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70. However, the TKB domain mutant mouse does show aspects of enhanced signaling that parallel those of the c-Cbl knockout mouse, but these involve the constitutive activation of Rac and not enhanced PTK activity. Furthermore, the enhanced signaling in CD4+CD8+ double positive thymocytes appears to be compensated by the selective down-regulation of CD3 on mature thymocytes and peripheral T cells from both strains of mutant c-Cbl mice.
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DOI：
10.1084/jem.185.2.263
发表时间：
1997-01-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kishimoto H;Sprent J
通讯作者：
Sprent J
影响因子：
10.5
作者：
KONTGEN, F;GRUMONT, RJ;GERONDAKIS, S
通讯作者：
GERONDAKIS, S
影响因子：
32.4
作者：
Labrecque, N;Whitfield, LS;Mathis, D
通讯作者：
Mathis, D
影响因子：
14.9
作者：
Schwenk, F;Baron, U;Rajewsky, K
通讯作者：
Rajewsky, K
DOI：
10.1084/jem.175.3.731
发表时间：
1992-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bendelac A;Matzinger P;Seder RA;Paul WE;Schwartz RH
通讯作者：
Schwartz RH