Retromer in Osteoblasts Interacts With Protein Phosphatase 1 Regulator Subunit 14C, Terminates Parathyroid Hormone's Signaling, and Promotes Its Catabolic Response

Autor: Jin-Xiu Pan, Wen Cheng Xiong, Fu Lei Tang, Lei Xiong, Lin Mei, Wen Fang Xia
Rok vydání: 2016
Předmět:
0301 basic medicine
Retromer
Vesicular Transport Proteins
lcsh:Medicine
Golgi Apparatus
Parathyroid hormone
Bone remodeling
Mice
VPS35
Protein Phosphatase 1
Receptor
Mice
Knockout
lcsh:R5-920
Chemistry
Intracellular Signaling Peptides and Proteins
Osteoblast
General Medicine
Protein Transport
medicine.anatomical_structure
Parathyroid Hormone
Bone Remodeling
lcsh:Medicine (General)
hormones
hormone substitutes
and hormone antagonists
Protein Binding
Signal Transduction
Research Paper
medicine.medical_specialty
PPP1R14C
Phosphatase
Bone Marrow Cells
Endosomes
Models
Biological
Bone and Bones
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Internal medicine
medicine
Animals
Humans
Receptor
Parathyroid Hormone
Type 1
PTH1R
Osteoblasts
lcsh:R
Protein phosphatase 1
Coculture Techniques
030104 developmental biology
Endocrinology
Biomarkers
Zdroj: EBioMedicine
EBioMedicine, Vol 9, Iss C, Pp 45-60 (2016)
ISSN: 2352-3964
Popis: Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function. VPS35 is expressed in osteoblast (OB)-lineage cells. VPS35-deficiency in OBs impaired PTH(1–34)-promoted PTH1R translocation to the trans-Golgi network, enhanced PTH(1–34)-driven signaling, and reduced PTH(1–34)'s catabolic response in culture and in mice. Further mechanical studies revealed that VPS35 interacts with not only PTH1R, but also protein phosphatase 1 regulatory subunit 14C (PPP1R14C), an inhibitory subunit of PP1 phosphatase. PPP1R14C also interacts with PTH1R, which is necessary for the increased endosomal PTH1R signaling and decreased PTH(1–34)'s catabolic response in VPS35-deficient OB-lineage cells. Taken together, these results suggest that VPS35 deregulates PTH1R-signaling likely by its interaction with PTH1R and PPP1R14C. This event is critical for the control of PTH(1–34)-signaling dynamics, which may underlie PTH-induced catabolic response and adequate bone remodeling.
Highlights • VPS35 terminates PTH(1-34)-induced cell surface and endosomal signalings • Osteoblastic VPS35 promotes PTH(1-34)-driven catabolic response • VPS35 interacts with PPP1R14C • PPP1R14C also interacts with PTH1R and promotes PTH(1-34)-induced endosomal signaling • PPP1R14C is necessary for the increased endosomal PTH1R signaling and decreased PTH(1-34)’s catabolic response in VPS35-deficient OB-lineage cells
Databáze: OpenAIRE
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