de Bock Charles E, Hughes Michael R, Snyder Kimberly, Alley Steven, Sadeqzadeh Elham, Dun Matt D, McNagny Kelly M, Molloy Timothy J, Hondermarck Hubert, Thorne Rick F
VIB Center for the Biology of Disease, Leuven, Belgium.
Hunter Cancer Research Alliance, University of Newcastle, Callaghan, Australia.
FEBS Lett. 2017 Feb;591(4):667-678. doi: 10.1002/1873-3468.12569. Epub 2017 Feb 16.
Mutations and ectopic FAT1 cadherin expression are implicated in a broad spectrum of diseases ranging from developmental disorders to cancer. The regulation of FAT1 and its downstream signalling pathways remain incompletely understood. We hypothesized that identification of additional proteins interacting with the FAT1 cytoplasmic tail would further delineate its regulation and function. A yeast two-hybrid library screen carried out against the juxtamembrane region of the cytoplasmic tail of FAT1 identified the E3 ubiquitin-protein ligase SH3RF1 as the most frequently recovered protein-binding partner. Ablating SH3RF1 using siRNA increased cellular FAT1 protein levels and stabilized expression at the cell surface, while overexpression of SH3RF1 reduced FAT1 levels. We conclude that SH3RF1 acts as a negative post-translational regulator of FAT1 levels.
突变和异位FAT1钙黏蛋白表达与从发育障碍到癌症等广泛的疾病有关。FAT1及其下游信号通路的调控仍未完全了解。我们推测，鉴定与FAT1细胞质尾部相互作用的其他蛋白质将进一步阐明其调控和功能。针对FAT1细胞质尾部近膜区域进行的酵母双杂交文库筛选确定E3泛素蛋白连接酶SH3RF1是最常回收的蛋白质结合伴侣。使用小干扰RNA（siRNA）消除SH3RF1可增加细胞FAT1蛋白水平并稳定其在细胞表面的表达，而SH3RF1的过表达则降低FAT1水平。我们得出结论，SH3RF1作为FAT1水平的负性翻译后调节因子发挥作用。
