Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting

Alonso, V.; Magyar, Clara E.; Wang, Bin; Bisello, Alessandro; Friedman, Peter A.

doi:10.1002/jbmr.494

Cited by 27 publications

(33 citation statements)

References 73 publications

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“…Ubiquitin is processed by an E1-activating enzyme, forming a thioester bond with ubiquitin that is required for transfer to E2-conjugating enzymes, and E3 ubiquitin ligases facilitate the covalent attachment of ubiquitin to substrate proteins. Ubiquitination is reversible, and the removal of ubiquitin is mediated by a family of deubiquitinating enzymes, including the ubiquitin-specific proteases (USPs) that are known to target ubiquitinated GPCRs (Milojevic et al, 2006;Alonso et al, 2011). Distinct types of ubiquitin conjugation are generated through the covalent attachment of a single ubiquitin moiety to an individual lysine or several lysine residues: monoubiquitination and multi-monoubiquitination (Fig.…”

Section: Introductionsupporting

confidence: 45%

“…The type 1 parathyroid hormone (PTH) receptor regulates bone growth and mineral ion balance and is responsive to distinct ligands. Stimulation with the activating ligand PTH(1-34) results in PTH receptor ubiquitination (Alonso et al, 2011). The PTH receptor is internalized and then recycled after deubiquitination.…”

Section: Gpcr Ubiquitination and Biased Agonismsupporting

confidence: 40%

“…The PTH receptor is internalized and then recycled after deubiquitination. In contrast, PTH receptor binding to the nonactivating ligand PTH(7-34) causes sustained ubiquitination and receptor degradation (Alonso et al, 2011). The different trafficking behaviors exhibited by the PTH receptor seem to be regulated by the deubiquitinating enzyme USP2, which is up-regulated in response to stimulation by the PTH(1-34) agonist (Alonso et al, 2011).…”

Section: Gpcr Ubiquitination and Biased Agonismsupporting

confidence: 39%

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Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Dores

Trejo

2012

Mol Pharmacol

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G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development.

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Section: Introductionsupporting

confidence: 45%

Section: Gpcr Ubiquitination and Biased Agonismsupporting

confidence: 40%

Section: Gpcr Ubiquitination and Biased Agonismsupporting

confidence: 39%

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Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Dores

Trejo

2012

Mol Pharmacol

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“…In response to PTH stimulation, the PTHR1 carboxyterminus becomes phosphorylated, promoting β-arrestin2 binding and receptor desensitization, followed by endocytosis to an internal compartment 137 . PTH induces a transient polyubiquitination of the PTHR1 by promoting coupled ubiquitination followed by deubiquitination through the rapid upregulation of the deubiquitinating enzyme USP2 138 . Following receptor endocytosis and desensitization, GPCRs usually re-sensitize and recycle back to the plasma membrane, which for the PTHR1 occurs within 2h after PTH stimulation 138 .…”

Section: Pthr1 Endocytosis and Desensitizationmentioning

confidence: 42%

“…PTH induces a transient polyubiquitination of the PTHR1 by promoting coupled ubiquitination followed by deubiquitination through the rapid upregulation of the deubiquitinating enzyme USP2 138 . Following receptor endocytosis and desensitization, GPCRs usually re-sensitize and recycle back to the plasma membrane, which for the PTHR1 occurs within 2h after PTH stimulation 138 . The PTHR1 is unique amongst GPCRs in that it does not require dephosphorylation or dissociation from β-arrestin in order to recycle back to the plasma membrane 139 .…”

Section: Pthr1 Endocytosis and Desensitizationmentioning

confidence: 42%

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Murray¹

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PTH is a critical regulator of serum phosphorus. We have previously shown that PTH decreases proximal tubule NpT2a mRNA expression through post‐transcriptional mechanisms, and that this effect can be reproduced by treatment with 8‐bromo‐cAMP, a PKA activator, but not phorbol myristate acetate, a PKC activator. We hypothesize that PKA is the primary mediator of NpT2a mRNA destabilization by PTH. To determine the contribution of each pathway to the PTH response, opossum kidney (OK) cells were treated with selective protein kinase inhibitors in the presence of PTH, and NpT2a mRNA expression was measured by qRT‐PCR. Pretreatment with 10µM PKC inhibitor peptide (PKCi) followed by 100nM PTH for 6h produced a 43.9% decrease in NpT2a mRNA versus PKCi alone. Pretreatment with 10µM H‐89, a PKA inhibitor, prevented the initial decrease in NpT2a mRNA by PTH but did not prevent the ultimate reduction. 8CPT‐2Me‐cAMP, a selective activator of Epac, failed to produce a decrease in NpT2a mRNA after 6h. We conclude that the initial effect of PTH on NpT2a mRNA is PKA‐dependent, whereas chronic regulation involves both the PKA and PKC pathways. Grant Funding Source: Support for this project is provided by VA to EDL.

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Ubiquitin‐Related Roles of β‐Arrestins in Endocytic Trafficking and Signal Transduction

Jean-Charles

Rajiv

Shenoy

2016

Journal Cellular Physiology

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The non-visual arrestins, β-arrestin1, and β-arrestin2 were originally identified as proteins that bind to seven-transmembrane receptors (7TMRs, also called G protein-coupled receptors, GPCRs) and block heterotrimeric G protein activation, thus leading to desensitization of transmembrane signaling. However, as subsequent discoveries have continually demonstrated, their functionality is not constrained to desensitization. They are now recognized for their critical roles in mediating intracellular trafficking of 7TMRs, growth factor receptors, ion transporters, ion channels, nuclear receptors, and non-receptor proteins. Additionally, they function as crucial mediators of ubiquitination of 7TMRs as well as other receptors and non-receptor proteins. Recently, emerging studies suggest that a class of proteins with predicted structural features of β-arrestins regulate substrate ubiquitination in yeast and higher mammals, lending support to the idea that the adaptor role of β-arrestins in protein ubiquitination is evolutionarily conserved. β-arrestins also function as scaffolds for kinases and transduce signals from 7TMRs through pathways that do not require G protein activation. Remarkably, the endocytic and scaffolding functions of β-arrestin are intertwined with its ubiquitination status; the dynamic and site specific ubiquitination on β-arrestin plays a critical role in stabilizing β-arrestin-7TMR association and the formation of signalosomes. This review summarizes the current findings on ubiquitin-dependent regulation of 7TMRs as well as β-arrestins and the potential role of reversible ubiquitination as a "biological switch" in signal transduction. J. Cell. Physiol. 231: 2071-2080, 2016. © 2016 Wiley Periodicals, Inc.

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Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting

Cited by 27 publications

References 73 publications

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Ubiquitination of G Protein-Coupled Receptors: Functional Implications and Drug Discovery

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

Ubiquitin‐Related Roles of β‐Arrestins in Endocytic Trafficking and Signal Transduction

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