Betacellulin-delta4, a novel differentiation factor for pancreatic beta-cells, ameliorates glucose intolerance in streptozotocin-treated rats.

Abstract

We previously described a novel alternatively spliced mRNA transcript of the betacellulin (BTC) gene. This splice isoform, termed BTC-delta4, 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-delta4 recombinantly to explore its biological function. When BTC-delta4 was expressed in COS-7 cells, it was secreted largely into the culture medium, in contrast to BTC. Unlike BTC, highly purified recombinant BTC-delta4 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-delta4 failed to stimulate DNA synthesis in Balb/c 3T3 and INS-1 cells. However, BTC-delta4 induced differentiation of pancreatic beta-cells; BTC-delta4 converted AR42J cells to insulin-producing cells. When recombinant BTC-delta4 was administered to streptozotocin-treated neonatal rats, it reduced the plasma glucose concentration and improved glucose tolerance. Importantly, BTC-delta4 significantly increased the insulin content, the beta-cell mass, and the numbers of islet-like cell clusters and PDX-1-positive ductal cells. Thus, BTC-delta4 is a secreted protein that stimulates differentiation of beta-cells in vitro and in vivo in an apparent ErbB1- and ErbB4-independent manner. The mechanism by which BTC-delta4 exerts this action on beta-cells remains to be defined but presumably involves an, as yet, unidentified unique receptor.

• Authors: Takeki Ogata, Andrew J Dunbar, Yoritsuna Yamamoto, Yuji Tanaka, Masaharu Seno, Itaru Kojima
• Journal: Endocrinology (Endocrinology) Vol. 146 Issue 11 Pg. 4673-81 (Nov 2005) ISSN: 0013-7227 [Print] United States
• PMID: 16081630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Betacellulin
• Blood Glucose
• Btc protein, mouse
• Btc protein, rat
• Intercellular Signaling Peptides and Proteins
• Intracellular Signaling Peptides and Proteins
• Recombinant Proteins
• Streptozocin
• ErbB Receptors
• Erbb4 protein, mouse
• Erbb4 protein, rat
• Receptor, ErbB-2
• Receptor, ErbB-4

Topics

• Animals
• Betacellulin
• Blood Glucose (metabolism)
• Cell Differentiation (drug effects)
• Cell Line
• ErbB Receptors (metabolism)
• Glucose Intolerance (chemically induced, physiopathology)
• Insulin-Secreting Cells (pathology)
• Intercellular Signaling Peptides and Proteins
• Intracellular Signaling Peptides and Proteins (metabolism, pharmacology)
• Mice
• Osmolar Concentration
• Rats
• Rats, Sprague-Dawley
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-4
• Recombinant Proteins (biosynthesis)
• Streptozocin