Sela Cheifetz

Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor system

We describe the primary structure of rat betaglycan, a polymorphic membrane-anchored proteoglycan with high affinity for transforming growth factor-beta (TGF-beta). As deduced from its cDNA sequence, the 853 amino acid core protein of betaglycan has an extracellular domain with clustered sites for potential attachment of glycosaminoglycan chains. These chains are dispensable for TGF-beta binding to the core protein. The transmembrane region and the short cytoplasmic tail of betaglycan are very similar to these regions in human endoglin, an endothelial cell membrane glycoprotein involved in intercellular recognition. The ectodomain of betaglycan can be released as a soluble proteoglycan; a potential cleavage site near the transmembrane region is identical to the highly regulated cleavage site of the membrane-anchored transforming growth factor-alpha precursor. The unique features of betaglycan suggest important roles in cell interaction with TGF-beta.

Novel activin receptors : distinct genes and alternative mRNA splicing generate a repertoire of serine/threonine kinase receptors

We have cloned ActR-IIB, which encodes four new activin receptor isoforms belonging to the protein serine/threonine kinase receptor family. Two of the ActR-IIB isoforms have higher affinity for activin A than the previously cloned activin receptor and differ from each other by the inclusion of an alternatively spliced segment in the cytoplasmic juxtamembrane region. A second alternative splicing event generates two additional receptor isoforms that lack a proline cluster in the external juxtamembrane region and have lower affinity for activin A. All isoforms bind inhibin A with low affinity. Thus, the repertoire of activin receptors includes species that differ in ligand binding affinity, cytoplasmic domain structure, or both. This receptor heterogeneity might underlie the sharply different responses that activin can elicit in a dose- or cell-specific manner.

Transforming growth factor-β receptors and binding proteoglycans

Summary Transforming growth factors-beta (TGFs-β) are representative of a superfamily whose members were first identified as regulators of morphogenesis and differentiation, and subsequently found to be structurally related. Other members of the family include the activins and inhibins, BMPs, MIS, the DPP-C gene product and Vg-1. When assayed by affinity-labelling techniques, TGFs-β bind to three distinct cell surface proteins which are present on most cells. These proteins are all of relatively low abundance but bind TGFs-β with affinities consistent with the biological potency of the factors. The Type I and Type II binding proteins are glycoproteins with estimated molecular weights of 53 and 73×103Mr, respectively. They both bind TGF-β1 significantly better than TGF-β2. The Type I receptor has been identified as the receptor which mediates many of the responses of TGFs-β, based on somatic cell genetic studies of epithelial cell mutants unresponsive to TGFs-β. Betaglycan is the third binding protein present on many, but not all, cell types and is a large proteoglycan (∼280×103Mr) with 100–120×103Mr, core proteins. A soluble form of this molecule is present in conditioned media of many cell lines and may be derived from the cell surface-associated molecule by cleavage of a small membrane anchor. Betaglycan binds TGF-β1 and TGF-β2 with similar affinity and this binding is to the core proteins, not the glycosaminoglycan side chains. This molecule may have a function in the localization and delivery or the clearance of activated TGFs-β. The molecular basis of TGF-β signalling is still largely unknown, but it is possible that one or more of these cell surface molecules signals via a novel mechanism, as the TGFs-β are biologically quite distinct from other factors that act via well-characterized signalling systems.