New roles for cripto in the assembly and localisation of nodal signalling platforms

The TGFβ family member Nodal is essential during development to allocate pluripotent cells to distinct germ layers and to establish the basic body plan. To establish a signaling gradient of the transcription factors Smad2 and Smad3, Nodal forms a complex with Activin receptors that is activated with the help of the glycosylphosphosphatidyl-inositol-anchored proteoglycans Cripto or Cryptic. To elucidate the underlying mechanism, we investigated whether Cripto regulates the proteolytic maturation and/or trafficking of Nodal precursor protein. We show that Cripto captures Nodal already during secretion, partly via the propeptide, and assembles a processing complex with the proprotein convertases Furin at the cell surface. Subsequently, Cripto mediates uptake of mature Nodal via a conclathrin, noncaveolar pathway to signaling endosomes. Our results suggest that Cripto is a receptor for proprotein convertases and couples Nodal processing and signaling in target cells