Co-receptor

A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell. Properties The term co-receptor is prominent in literature regarding signal transduction, the process by which external stimuli regulate internal cellular functioning. The key to optimal cellular functioning is maintained by possessing specific machinery that can carry out tasks efficiently and effectively. Specifically, the process through which intermolecular reactions forward and amplify extracellular signals across the cell surface has developed to occur by two mechanisms. First, cell surface receptors can directly transduce signals by possessing both serine and threonine or simply serine in the cytoplasmic domain. They can also transmit signals through adaptor molecules through their cytoplasmic domain which bind to signalling motifs. Secondly

The Role of Nodal Processing in Pluripotent Progenitors

Anja Dietze

Nodal and its co-receptors of the EGF-CFC family are essential during chordate development, both to maintain pluripotent progenitor cells and to subsequently coordinate their allocation to the different germ layers. How these distinct Nodal activities are kept in balance is unknown. Previous work in our laboratory established that the Nodal proprotein must be cleaved by proprotein convertases (PC) to induce itself on time in the mouse epiblast. However, expression of a knock-in allele encoding a PC-resistant mutant Nodal precursor (Nr) is sufficient to induce a subset of Nodal target genes during gastrulation, including Fgf4 in the epiblast, and Bmp4 in extraembryonic ectoderm (ExE). Here, I extend these findings by showing that these NodalNr/Nr embryos also partially maintain a panel of trophoblast stem cell (TSC) markers. To better define how Nodal maintains pluripotency and how it might signal to TSCs in the ExE, and as a means to genetically uncouple Nodal production from processing, I treated cultured TSCs and NodallacZ/lacZ embryonic stem cells (ESCs) with recombinant Nodal or with cleavage-resistant mutant Nodal precursor. I show that recombinant mature Nodal stimulates Smad2 phosphorylation in both ESCs and TSCs, even though the latter do not express Nodal coreceptors of the EGF-CFC family. In contrast, recombinant Nr failed to activate the canonical Smad pathway in either cell type, and hence preferentially stimulated Jnk and p38 MAPK signaling. Yet, none of these activities were sufficient to promote self-renewal of mouse ESCs or TSCs under any of the culture conditions examined. Using lentiviral overexpression of constitutively active receptors with mutations in the Smad2,3 binding site, I observed that TSC stemness apparently can be maintained independently of Smad2,3 activation. These results suggest that mature Nodal or its unprocessed precursor likely promote the self-renewal of TSCs in vivo through a non-canonical, Smad-independent signaling pathway, but that available recombinant proteins for unknown reasons cannot fully mimic this activity in vitro, at least under the conditions examined.

EPFL2011

Cripto localizes nodal at the limiting membrane of early endosomes

Stéphane Baflast, Daniel Constam

Cripto is a glycosylphosphatidylinositol (GPI)-anchored co-receptor of Nodal and several other transforming growth factor-beta (TGF-beta) family ligands. It contains an epidermal growth factor (EGF)-like motif and a Cripto-FRL1-Cryptic (CFC) domain, which are conserved in a family of EGF-CFC proteins. The EGF domain is thought to recruit Nodal, whereas the CFC domain mediates binding to activin receptor-like kinase 4 (ALK4). We found that the EGF-like motif of Cripto was not essential for its binding to Nodal. However, through residues phenylalanine 78 and glycine 71, Cripto enriched Nodal at the limiting membrane of early endosomes. Similarly, residues in the CFC domain that mediate binding of Cripto to ALK4 were required to attenuate sequestration of Nodal in the endosomal lumen. Thus, we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors. To our knowledge, Cripto is the first GPI-anchored protein shown to control intraendosomal sorting of its associated cargo.

2008

The Role of Nodal Processing in Pluripotent Progenitors

Anja Dietze

EPFL2011

The Role of Nodal Processing in Pluripotent Progenitors

Interactions of CCR5, the Main HIV Coreceptor, with Rantes and Other Ligands

Cripto localizes nodal at the limiting membrane of early endosomes

Cripto localizes nodal at the limiting membrane of early endosomes

The Role of Nodal Processing in Pluripotent Progenitors

Interactions of CCR5, the Main HIV Coreceptor, with Rantes and Other Ligands