Human ROBO1 is cleaved by metalloproteinases and γ-secretase and migrates to the nucleus in cancer cells

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• 作者：Motoaki Seki ; Akira Watanabe ; Satoshi Enomoto ; Takeshi Kawamura ; Hirotaka Ito ; Tatsuhiko Kodama ; Takao Hamakubo ; Hiroyuki Aburatani
• 关键词：ROBO1 ; Metalloproteinase ; γ ; -Secretase ; Regulated intramembrane proteolysis
• 刊名：FEBS Letters
• 出版年：2010
• 出版时间：2 July 2010
• 年：2010
• 卷：584
• 期：13
• 页码：2909-2915
• 全文大小：632 K

文摘

ROBO1 is a receptor mediating Slit-induced repulsive action on axon guidance and differentially expressed in human cancers. Although ROBO1 ectodomain has been detected, the cleavage site had not been determined. In this study we identified the precise cleavage site of ROBO1. We also report multi-step proteolysis of ROBO1 by metalloproteinases and γ-secretase, producing two carboxy-terminal fragments, ROBO1-CTF1 at 129-kDa and ROBO1-CTF2 at 118-kDa. We have further demonstrated nuclear accumulation of ROBO1, which is abolished by either a metalloproteinase inhibitor TAPI-1 or a γ-secretase inhibitor L-685,458. ROBO1 may function beyond the receptor through stepwise cleavages and translocation to the nucleus.