Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Arrestins / genetics
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Arrestins / metabolism
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Bone Density / genetics
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Bone Remodeling / drug effects
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Bone Remodeling / physiology*
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Cell Count
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Cells, Cultured
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Collagen Type I / blood
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Endocytosis / drug effects
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Endocytosis / genetics
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Gene Expression / genetics
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Humans
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Leg Bones / drug effects
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Leg Bones / pathology
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Male
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Mice
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Mice, Knockout
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Mutation / physiology
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Osteoblasts / metabolism
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Osteoblasts / pathology
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Osteocalcin / blood
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Osteoclasts / pathology
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Parathyroid Hormone / antagonists & inhibitors
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Parathyroid Hormone / metabolism
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Parathyroid Hormone / pharmacology
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Peptide Fragments / pharmacology
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Peptides / blood
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Protein Binding / drug effects
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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Protein Multimerization / drug effects
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Protein Multimerization / physiology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RANK Ligand / metabolism
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RNA, Small Interfering / genetics
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Receptor, Parathyroid Hormone, Type 1 / genetics
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Receptor, Parathyroid Hormone, Type 1 / metabolism*
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Smad Proteins / metabolism
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beta-Arrestins
Substances
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Arrestins
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Collagen Type I
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Cyclic AMP Response Element-Binding Protein
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Parathyroid Hormone
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Peptide Fragments
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Peptides
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RANK Ligand
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RNA, Small Interfering
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Receptor, Parathyroid Hormone, Type 1
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Tnfsf11 protein, mouse
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beta-Arrestins
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collagen type I trimeric cross-linked peptide
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parathyroid hormone (7-34)
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Osteocalcin
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Cyclic AMP
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II