The ABC of BTC: Structural properties and biological roles of betacellulin

•Betacellulin binds the EGFR and a variety of EGFR/ERBB receptor combinations.•Betacellulin stimulates β-cell growth, reproduction, and other physiological processes.•Betacellulin-deficient mice grow normally, probably due to functional compensation by other EGFR ligands.•Overexpression of betacellulin in transgenic mice results in numerous complex phenotypes.

Betacellulin was initially detected as a growth-promoting factor in the conditioned medium of a mouse pancreatic β-cell tumor cell line. Sequencing of the purified protein and of the cloned cDNA supported the assumption that betacellulin is a new ligand of the epidermal growth factor receptor (EGFR), which was later confirmed experimentally. As a typical EGFR ligand, betacellulin is expressed by a variety of cell types and tissues, and the soluble growth factor is proteolytically cleaved from a larger membrane-anchored precursor. Importantly, BTC can – in addition to the EGFR – bind and activate all possible heterodimeric combinations of the related ERBB receptors including the highly oncogenic ERBB2/3 dimer, as well as homodimers of ERBB4. While a large number of studies attest a role for betacellulin in the differentiation of pancreatic β-cells, the last decade witnessed the association of betacellulin with a large number of additional biological processes, ranging from reproduction to the control of neural stem cells.