Betacellulin (BTC) is an epidermal-growth-factor-like ligand that, similar to other members of this large family of soluble ligands, is produced by proteolytic cleavage of a transmembrane precursor (proBTC). BTC binds to ErbB1 and ErbB4, and facilitates the function, survival and regeneration of pancreatic β-cells – but what happens to the rest of proBTC? Peter Dempsey and colleagues begin to answer this question on page 2319, where they show that proBTC is cleaved by the disintegrin ADAM10 to produce the cytoplasmic tail fragment of BTC (BTC-CTF), and that BTC-CTF then undergoes intramembrane processing by γ-secretase to generate an intracellular-domain fragment, BTC-ICD. Other experiments indicate that the cytoplasmic domain of proBTC is palmitoylated and that this palmitoylation is both implicated in the stability and γ-secretase processing of BTC-CTF and needed for the nuclear-membrane localization of BTC-ICD. Finally, the authors show that BTC-ICD inhibits the growth of conditionally immortalized mouse pancreatic epithelial cells through receptor-independent reverse signalling. These new insights into the function of BTC-ICD might help to improve the efficacy of BTC gene therapy, which is currently being investigated as a treatment for diabetes.
- © 2010.