Disruption of ?-catenin binding to parathyroid hormone (PTH) receptor inhibits PTH-stimulated ERK1/2 activation.

ABSTRACT: The type I parathyroid hormone receptor (PTH1R) mediates PTH and PTH-related protein (PTHrP) actions on extracellular mineral ion homeostasis and bone remodeling. These effects depend in part on the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Sequences located within or at the carboxyl-terminus of PTH1R control its activation and trafficking. ?-catenin regulates PTH1R signaling and promotes chondrocyte hypertrophy through binding to the intracellular carboxyl-terminal region of the receptor. How the interaction of PTH1R with ?-catenin affects PTH-stimulated ERK1/2 is unknown. In the present study, human embryonic kidney 293 (HEK293) cells, which do not express the PTH1R, were used to investigate whether the disruption of ?-catenin binding to PTH1R affects PTH-stimulated ERK1/2 activation. We demonstrated that ?-catenin interacted with wild-type PTH1R but this interaction was markedly reduced with mutant PTH1R (L584A/L585A). PTH stimulated less cAMP formation and increased more intracellular calcium in HEK293 cells transfected with wild-type PTH1R compared with mutant PTH1R, indicating ?-catenin switches PTH1R signaling from G?s activation to G?q signaling. In addition, ERK1/2 activation in HEK293 cells transfected with PTH1R exhibited time and concentration dependence. PTH-stimulated ERK1/2 activation was mostly mediated through G?q/PLC signaling pathway. Importantly, transfection of mutant PTH1R decreased PTH-induced ERK1/2 activation by inhibiting G?q-mediated signaling. This study shows for the first time that the interference of ?-catenin binding to PTH1R inhibits PTH-stimulated ERK1/2 phosphorylation.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC4509838 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature