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
N1 - Publisher Copyright:
© 2016 Pal et al.
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.
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U2 - 10.1083/jcb.201506132
DO - 10.1083/jcb.201506132
M3 - Article
C2 - 27002170
AN - SCOPUS:84978103999
SN - 0021-9525
VL - 212
SP - 861
EP - 875
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 7
ER -