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TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling
Tao Qiu1, Xiangwei Wu, Fengjie Zhang
1Department of Orthopaedic Surgery, Johns Hopkins Medical Institution, 720 Rutland Avenue, Ross Building 232, Baltimore, Maryland 21205, USA.
None:
Parathyroid hormone (PTH) regulates calcium homeostasis and bone metabolism by activating PTH type I receptor (PTH1R). Here we show that transforming growth factor (TGF)-beta type II receptor (TbetaRII) forms an endocytic complex with PTH1R in response to PTH and regulates signalling by PTH and TGF-beta. TbetaRII directly phosphorylates the PTH1R cytoplasmic domain, which modulates PTH-induced endocytosis of the PTH1R-TbetaRII complex. Deletion of TbetaRII in osteoblasts increases the cell-surface expression of PTH1R and augments PTH signalling. Conditional knockout of TbetaRII in osteoblasts in mice results in a high bone mass with increased trabecular bone and decreased cortical bone, similar to the bone phenotype in mice expressing a constitutively active PTH1R. Disruption of PTH signalling by injection of PTH(7-34) or ablation of PTH1R rescues the bone phenotype of TbetaRII knockout mice. These studies reveal a previously unrecognized function for TbetaRII and a mechanism for integration of PTH and local growth factor at the membrane receptor level.
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