Utrophin is a widely expressed paralogue of dystrophin, the protein responsible for
Duchenne muscular dystrophy. Utrophin is a large spectrin-like protein whose C-terminal
domain mediates anchorage to a laminin receptor, dystroglycan (DG). The rod domain,
composed of 22 spectrin-like repeats, connects the N-terminal actin-binding domain
and the C-terminal DG binding domain, and thus mediates molecular linkage between
intracellular F-actin and extracellular basement membrane. Previously, we demonstrated
that a cell polarity-regulating kinase, PAR-1b, interacts with the utrophin-DG complex,
and positively regulates the interaction between utrophin and DG. In this study, we
demonstrate that the 8th and 9th spectrin-like repeats (R8 and R9) of utrophin cooperatively
form a PAR-1b-interacting domain, and that Ser1258 within R9 is specifically phosphorylated
by PAR-1b. Substitution of Ser1258 to alanine reduces the interaction between utrophin
and DG, suggesting that the Ser1258 phosphorylation contributes to the stabilization
of the utrophin-DG complex. Interestingly, PAR-1b also binds and phosphorylates R8-9
of dystrophin, and colocalizes with dystrophin at the skeletal muscle membrane. These
results reveal a novel function of the rod domain of utrophin beyond that of a passive
structural linker connecting the N- and C-terminal domain.
Copyright 2009 Elsevier Inc. All rights reserved.