title: Human ROBO1 is cleaved by metalloproteinases and gamma-secretase and migrates to the nucleus in cancer cells.
abstract: 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 gamma-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 gamma-secretase inhibitor L-685,458. ROBO1 may function beyond the receptor through stepwise cleavages and translocation to the nucleus.
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Seki
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Enomoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ito
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007976:Leupeptins / Q000494:pharmacology; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D053719:Tandem Mass Spectrometry; D000097905:Roundabout Proteins
chemical_list: D053829:Amyloid Precursor Protein Secretases; D002219:Carbamates; D004151:Dipeptides; D006877:Hydroxamic Acids; D007976:Leupeptins; D045726:Metalloproteases; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C410009:L 685458; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde