Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium

Kasturi Pal, Sun hee Hwang, Bandarigoda Somatilaka, Hemant Badgandi, Peter K. Jackson, Kathryn DeFea, Saikat Mukhopadhyay

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein-coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves ß-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161-ß-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

Original languageEnglish (US)
Pages (from-to)861-875
Number of pages15
JournalJournal of Cell Biology
Volume212
Issue number7
DOIs
StatePublished - Mar 28 2016

Fingerprint

Arrestin
Cilia
G-Protein-Coupled Receptors
Hedgehogs
Membrane Proteins
G-Protein-Coupled Receptor Kinases
Clathrin
Endocytosis
Vertebrates
Homeostasis
Down-Regulation

ASJC Scopus subject areas

  • Cell Biology

Cite this

Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. / Pal, Kasturi; Hwang, Sun hee; Somatilaka, Bandarigoda; Badgandi, Hemant; Jackson, Peter K.; DeFea, Kathryn; Mukhopadhyay, Saikat.

In: Journal of Cell Biology, Vol. 212, No. 7, 28.03.2016, p. 861-875.

Research output: Contribution to journalArticle

Pal, Kasturi ; Hwang, Sun hee ; Somatilaka, Bandarigoda ; Badgandi, Hemant ; Jackson, Peter K. ; DeFea, Kathryn ; Mukhopadhyay, Saikat. / Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. In: Journal of Cell Biology. 2016 ; Vol. 212, No. 7. pp. 861-875.
@article{7425bff7fc5b4f53b5946fed7cb5bf26,
title = "Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium",
abstract = "Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein-coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves {\ss}-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161-{\ss}-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.",
author = "Kasturi Pal and Hwang, {Sun hee} and Bandarigoda Somatilaka and Hemant Badgandi and Jackson, {Peter K.} and Kathryn DeFea and Saikat Mukhopadhyay",
year = "2016",
month = "3",
day = "28",
doi = "10.1083/jcb.201506132",
language = "English (US)",
volume = "212",
pages = "861--875",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium

AU - Pal, Kasturi

AU - Hwang, Sun hee

AU - Somatilaka, Bandarigoda

AU - Badgandi, Hemant

AU - Jackson, Peter K.

AU - DeFea, Kathryn

AU - Mukhopadhyay, Saikat

PY - 2016/3/28

Y1 - 2016/3/28

N2 - Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein-coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves ß-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161-ß-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

AB - Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein-coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves ß-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161-ß-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

UR - http://www.scopus.com/inward/record.url?scp=84978103999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978103999&partnerID=8YFLogxK

U2 - 10.1083/jcb.201506132

DO - 10.1083/jcb.201506132

M3 - Article

C2 - 27002170

AN - SCOPUS:84978103999

VL - 212

SP - 861

EP - 875

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 7

ER -