TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling.
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.
Qiu
Tao
T
Department of Orthopaedic Surgery, Johns Hopkins Medical Institution, 720 Rutland Avenue, Ross Building 232, Baltimore, Maryland 21205, USA.
Wu
Xiangwei
X
Zhang
Fengjie
F
Clemens
Thomas L
TL
Wan
Mei
M
Cao
Xu
X
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D015519:Bone Density / Q000235:genetics; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D024042:Collagen Type I / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007867:Leg Bones / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000473:pathology; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000097:blood; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D024042:Collagen Type I; D017362:Cyclic AMP Response Element-Binding Protein; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010455:Peptides; D053245:RANK Ligand; D034741:RNA, Small Interfering; D044168:Receptor, Parathyroid Hormone, Type 1; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C505689:Tnfsf11 protein, mouse; D000071557:beta-Arrestins; C052929:collagen type I trimeric cross-linked peptide; C058350:parathyroid hormone (7-34); D015675:Osteocalcin; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II