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Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation
Author(s) -
Blanchet MarieHélène,
Le Good J Ann,
Mesnard Daniel,
Oorschot Viola,
Baflast Stéphane,
Minchiotti Gabriella,
Klumperman Judith,
Constam Daniel B
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.174
Subject(s) - biology , furin , proprotein convertases , microbiology and biotechnology , ethnically diverse , genetics , biochemistry , environmental health , enzyme , lipoprotein , ldl receptor , cholesterol , medicine , population
The glycosylphosphatidylinositol (GPI)‐anchored proteoglycan Cripto binds Nodal and its type I receptor Alk4 to activate Smad2,3 transcription factors, but a role during Nodal precursor processing has not been described. We show that Cripto also binds the proprotein convertases Furin and PACE4 and localizes Nodal processing at the cell surface. When coexpressed as in early embryonic cells, Cripto and uncleaved Nodal already associated during secretion, and a Cripto‐interacting region in the Nodal propeptide potentiated the effect of proteolytic maturation on Nodal signalling. Disruption of the trans‐Golgi network (TGN) by brefeldin A blocked secretion, but export of Cripto and Nodal to the cell surface was not inhibited, indicating that Nodal is exposed to extracellular convertases before entering the TGN/endosomal system. Density fractionation and antibody uptake experiments showed that Cripto guides the Nodal precursor in detergent‐resistant membranes to endocytic microdomains marked by GFP–Flotillin. We conclude that Nodal processing and endocytosis are coupled in signal‐receiving cells.