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Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation
Marie-Hélène Blanchet1, J Ann Le Good, Daniel Mesnard
1Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland.
The EMBO Journal
|September 6, 2008
Summary
Cripto protein guides Nodal precursor processing at the cell surface by binding convertases. This coupling of Nodal maturation and endocytosis is crucial for signal-receiving cells.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Cripto, a GPI-anchored proteoglycan, binds Nodal and its receptor Alk4, activating Smad2,3 transcription factors.
- The role of Cripto in Nodal precursor processing has not been previously described.
Purpose of the Study:
- To investigate the role of Cripto in Nodal precursor processing.
- To elucidate the mechanism by which Cripto influences Nodal maturation and signaling.
Main Methods:
- Co-expression of Cripto and Nodal in early embryonic cells.
- Treatment with brefeldin A to disrupt the trans-Golgi network (TGN).
- Density fractionation and antibody uptake experiments using GFP-Flotillin.
Main Results:
- Cripto binds proprotein convertases Furin and PACE4, localizing Nodal processing to the cell surface.
- Cripto and uncleaved Nodal associate during secretion, with a Nodal propeptide region enhancing maturation.
- Nodal is exposed to extracellular convertases before TGN/endosomal system entry.
- Cripto directs Nodal precursor within detergent-resistant membranes to endocytic microdomains.
Conclusions:
- Nodal processing and endocytosis are coupled events in signal-receiving cells.
- Cripto plays a critical role in coordinating Nodal maturation and cellular uptake for effective signaling.
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