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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Ogata T,Dunbar AJ,Yamamoto Y,Tanaka Y,Seno M,Kojima I

doi

10.1210/en.2005-0456

subject

Has Abstract

pub_date

2005-11-01 00:00:00

pages

4673-81

issue

11

eissn

0013-7227

issn

1945-7170

pii

en.2005-0456

journal_volume

146

pub_type

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