A fibulin-1 homolog interacts with an ADAM protease that controls cell migration in C. elegans.
ADAM (a disintegrin and metalloprotease) family proteins play important roles in animal development and pathogenesis. In C. elegans, a secreted ADAM protein, MIG-17, acts from outside the gonad to control the migration of gonadal distal tip cells (DTCs) that promote gonad morphogenesis. Here, we report that dominant mutations in the fbl-1 gene encoding fibulin-1 spliced isoforms, which are calcium binding extracellular matrix proteins, bypass the requirement for MIG-17 activity in directing DTC migration. Specific amino acid substitutions in the third EGF-like motif of one of the two isoforms, FBL-1C, which corresponds to mammalian fibulin-1C, suppress mig-17 mutations. FBL-1C is synthesized in the gut cells and localizes strongly to the gonadal basement membrane in a MIG-17-dependent manner. Localization of mutant FBL-1C is weaker than that of the wild-type protein and is insensitive to MIG-17 activity, suggesting that it gains a novel function that compensates for its reduced molecular density. We propose that proteolysis by MIG-17 recruits FBL-1C to the gonadal basement membrane, where it is required for the guidance of DTCs, and that mutant FBL-1C acts in a manner that mimics the downstream events of MIG-17-mediated proteolysis.
Kubota
Yukihiko
Y
RIKEN Center for Developmental Biology, Chuo-ku, Kobe 650-0047, Japan.
Kuroki
Rie
R
Nishiwaki
Kiyoji
K
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D017931:DNA Primers; D019483:Disintegrins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006066:Gonads / Q000254:growth & development*; D008666:Metalloendopeptidases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D038081:Organogenesis / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D020033:Protein Isoforms; D015398:Signal Transduction / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D017931:DNA Primers; D019483:Disintegrins; C410348:MIG-17 protein, C elegans; D020033:Protein Isoforms; C060820:fibulin; D008666:Metalloendopeptidases