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.
Department of Orthopaedic Surgery, Johns Hopkins Medical Institution, 720 Rutland Avenue, Ross Building 232, Baltimore, Maryland 21205, USA.
Tao
T
Qiu
Xiangwei
X
Wu
Fengjie
F
Zhang
Thomas L
TL
Clemens
Mei
M
Wan
Xu
X
Cao
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