Zhang Wenying, Shao Yuan, Fang Deyu, Huang Jianyong, Jeon Myung-Shin, Liu Yun-Cai
La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
J Biol Chem. 2003 Jun 27;278(26):23978-83. doi: 10.1074/jbc.M212671200. Epub 2003 Apr 15.
It was previously reported that Cbl-b associates with Crk-L in Jurkat T cells. However, the physiological significance of such association remains unclear. Here we examined a regulatory role of Cbl-b in Crk-L-C3G signaling pathway. We found that Cbl-b associates with, and induces, ubiquitin conjugation to Crk-L, which requires a functional RING finger. Cbl-b deficiency does not affect Crk-L stability, but its association with C3G. In Cbl-b-/- T cells, the interaction between Crk-L and C3G, and the activity of the small GTPase Rap1, are increased. Cbl-b-/- T cells also display increased adhesion and cell surface binding to ICAM-1, a finding that is supported by the enhanced clustering of LFA-1 in Cbl-b-/- T cells in response to TCR stimulation. Thus, Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells.
先前有报道称，在Jurkat T细胞中Cbl-b与Crk-L相互关联。然而，这种关联的生理意义仍不清楚。在此，我们研究了Cbl-b在Crk-L-C3G信号通路中的调节作用。我们发现Cbl-b与Crk-L相互关联并诱导其泛素化缀合，这需要一个功能性的环状结构域。Cbl-b缺陷不影响Crk-L的稳定性，但影响其与C3G的关联。在Cbl-b基因敲除的T细胞中，Crk-L与C3G之间的相互作用以及小GTP酶Rap1的活性增强。Cbl-b基因敲除的T细胞还表现出与ICAM-1的黏附增加以及细胞表面结合增加，这一发现得到了Cbl-b基因敲除的T细胞中LFA-1在TCR刺激下增强聚集的支持。因此，Cbl-b在T细胞中Crk-L-C3G介导的Rap1和LFA-1激活中起负性作用。
