Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression
Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression
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DOI：
10.1038/nsmb1290
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发表时间：
2007-09-01
影响因子：
16.8
通讯作者：
Rossman, Kent L.
中科院分区：
文献类型：
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作者：
Mitin, Natalia;Betts, Laurie;Rossman, Kent L.
Rho鸟嘌呤核苷酸交换因子ASEF的自身抑制通过与APC肿瘤抑制因子的相互作用而减轻。在这里，我们表明，在ASEF中APC的犰狳重复序列与“核心APC结合”（CAB）基序的结合，或ASEF的SH3结构域的截短，缓解了自身抑制，允许特异性激活CDC42。自抑制ASEF的结构测定表明，SH3结构域与催化DH和PH结构域形成广泛的界面，以阻碍CDC42的结合和激活，CAB基序位于SH3结构域附近，以促进APC的激活。在结肠直肠癌细胞系中，全长但非截短的APC以ASEF依赖性方式激活CDC42以抑制锚定非依赖性生长。因此，我们提出了一个模型，其中ASEF作为一个肿瘤抑制因子激活时，APC和失活的ASEF突变或APC截断促进肿瘤发生。
Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a ` core APC- binding' ( CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding and activation of CDC42, and the CAB motif is positioned adjacent to the SH3 domain to facilitate activation by APC. In colorectal cancer cell lines, full- length, but not truncated, APC activates CDC42 in an ASEF- dependent manner to suppress anchorage independent growth. We therefore propose a model in which ASEF acts as a tumor suppressor when activated by APC and inactivation of ASEF by mutation or APC truncation promotes tumorigenesis.