We previously described a novel alternatively spliced mRNA transcript of the betacellulin (BTC) gene. This splice isoform, termed BTC-δ4, lacks the C-loop of the epidermal growth factor motif and the transmembrane domain as a result of exon 4 'skipping'. In this study, we expressed BTC-δ4 recombinantly to explore its biological function. When BTC-δ4 was expressed in COS-7 cells, it was secreted largely into the culture medium, in contrast to BTC. Unlike BTC, highly purified recombinant BTC-δ4 produced in Escherichia coli failed to bind or induce tyrosine phosphorylation of either ErbB1 or ErbB4, nor did it antagonize the binding of BTC to these receptors. Consistent with this, BTC-δ4 failed to stimulate DNA synthesis in Balb/c 3T3 and INS-1 cells. However, BTC-δ4 induced differentiation of pancreatic β-cells; BTC-δ4 converted AR42J cells to insulin-producing cells. When recombinant BTC-δ4 was administered to streptozotocin-treated neonatal rats, it reduced the plasma glucose concentration and improved glucose tolerance. Importantly, BTC-δ4 significantly increased the insulin content, the β-cell mass, and the numbers of islet-like cell clusters and PDX-1-positive ductal cells. Thus, BTC-δ4 is a secreted protein that stimulates differentiation of β-cells in vitro and in vivo in an apparent ErbB1- and ErbB4-independent manner. The mechanism by which BTC-δ4 exerts this action on β-cells remains to be defined but presumably involves an, as yet, unidentified unique receptor.
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