UNC5B is an isoform-dependent target for ectodomain shedding.

Ectodomain shedding (shedding) is a processing mechanism that cleaves the juxtamembrane region of membrane proteins and solubilizes almost the entire extracellular domain. Shedding irreversibly regulates the localization and function of membrane proteins; however, its physiological role is not fully understood. Previously, we showed that the shedding susceptibility of multiple membrane proteins is altered by skipping or inclusion of skipping exon(s) that encode their juxtamembrane region. In this study, we screened the skipping exon encoding the juxtamembrane region of membrane proteins and found that the shedding susceptibility of UNC5B, a Netrin-1 receptor, is altered by skipping or inclusion of the skipping exon encoding its juxtamembrane region. These results raise the possibility that the biological phenomena involving UNC5B, including neural circuit formation, angiogenesis and cancer development, are regulated by shedding in a splice isoform-dependent manner.