New insights into mechanisms of nuclear translocation of G-protein coupled receptors

Figures & data

Figure 1. Subcellular GPCR trafficking occurs via vesicular transport mechanisms which are regulated by members of Ras superfamily of small GTPases. Upon binding to its ligand at PM, 1) full-length GPCRs (e.g., F2rl1 and oxytocin receptor) can undergo agonist-induced nuclear translocation by importins and sorting nexins^21,22 or 2) can be recycled back by recycling Rabs (e.g., Rab 4, 11) or 3) targeted for degradation by proteasomes/lysosomes, the process regulated by Rab 7 and sorting nexin 1., 4) In case of the frizzed 2 receptor, its intracellular C-terminus is cleaved off by the action of cellular proteases and only C-terminus is then translocated to nucleus by importins and Ran GTPase.⁶⁹ Lastly, agonist-independent translocation of GPCRs directly from TGN 5) and 6) is controlled by rab/arf GTPases and (in case of nuclear translocation 6)) importins as well (Rab11a and importin-5 in case of the platelet-activating factor receptor).³⁶ More research is needed to understand trafficking of GPCRs between nuclear membranes and their orientation of at the NE.

Table 1. Known mechanisms and receptor motifs required for nuclear translocation of GPCRs.

GPCR	Mechanisms of Translocation and GPCR motifs (if known) required for Nuclear Localization	Endogenous Nuclear Localization	Reference
Adrenoceptors α 1A and 1B	α 1A and 1B receptors contain bipartite and arginine-rich NLS respectively, both within their C-termini.	Adult mouse cardiac myocytes	^Citation77
Angiotensin II receptor type 1	The C-terminal monopartite NLS is required for Angiotensin-II induced nuclear translocation of the type-1 receptor in rat neurons and human vascular smooth muscle cells.	Primary rat neurons (hypothalamus and brain stem), human vascular smooth muscle cells	^Citation31,Citation78
Apelin receptor	Agonist independent nuclear localization, the receptor contains monopartite NLS in its 3^rd intracellular loop.	Human cerebellar and hypothalamic neurons	^Citation32
Bradykinin receptor B2	Agonist-independent localization, C-terminal NLS.	Rat hepatocytes	^Citation32,Citation71
Chemokine receptors- C-C motif chemokine receptor 2 (CCR2) and C-X-C motif chemokine receptor 4 (CXCR4)	Both receptors undergo transportin 1-mediated nuclear translocation. CXCR4 contains a conserved functional NLS “RPRK” between amino acid residues 146 and 149.	Prostate and renal cancer cell lines (CXCR4)	^Citation79,Citation42
Cysteinyl leukotriene receptor 1	Bipartite NLS in its C-terminus between residues 310–324.	Colorectal adenocarcinoma cells	^Citation34
Endothelin receptor type A and type B	Both Type A and Type B endothelin receptors contain putative NLS in their C-terminus.^Citation32 However; functional role of the motifs hasn't been tested yet.	Human aortic vascular smooth cells, human ventricular endocardial endothelial cells (EECs), rat ventricular cardiomyocytes	^Citation80-Citation82
F2R like trypsin receptor 1	Agonist-induced nuclear localization is governed by Snx11, Importins β1, α3 and α5. Both NLS motifs (present in 1st and 3rd intracellular loops) and C-terminus of the receptor are required.	Retinal ganglion neurons (RGC)	^Citation21
Formyl peptide receptor 2	Human FPR2 contains a functional NLS in its 3^rd intracellular loop between residues 227 and 231.	Lung and gastric cancer cell lines	^Citation33
Frizzled receptor 2	C-terminus of drosophila Frizzled 2 receptor gets cleaved after ligand stimulation at PM and is translocated to the nucleus by Impβ11 and Impα2.	Drosophila muscle cells	^Citation69,Citation83
Lysophosphatidic acid receptor 1	Agonist-independent. Nuclear localization is regulated by integrin signaling and requires action Rho kinase in PC12 cells.	Piglet brain microvascular endothelial cells, PC12, human bronchial epithelial cells	^Citation73,Citation74
Melanocortin 2 receptor (MC2R)	MC2R directly interacts with nucleoporin 50 (NUP50) and Nup50-MC2R complex undergoes agonist-induced nuclear translocation from the PM.	Human adrenocortical epithelial cell-line (H295R)	^Citation84
Oxytocin receptor	Agonist-induced nuclear translocation is regulated by transportin 1 and β arrestins.	Primary mouse osteoblasts and MC3T3.E1 preosteoclastic cells	^Citation22
Parathyroid hormone receptor 1	The nucleocytoplasmic shuttling is governed by Importins α1 and β.	Rat (ROS 17/2.8) and human (SaOS-2) osteosarcoma cell-lines, mouse pre-osteoblast cell-line (MC3T3-E1)	^Citation41
Platelet-activating factor receptor	Nuclear localization is regulated by Rab11a and Importin5. Internalization motif between 311 and 330 residues in C-terminus of the receptor is required. Exogenous stimulation or endogenous agonist production are not needed.	Piglet brain microvascular endothelial cells and human retinal microvascular endothelial cells	^Citation35,Citation36
Sphingosine-1-phosphate receptor 1	Agonist-induced translocation	Human umbilical vein endothelial cells	^Citation74
VIP and PACAP receptor 1	Exogenous agonist (VIP) stimulation increases nuclear localization VIPR1 but not VIPR2.	Human breast cancer cell-lines (T47D and MDA-MB-468)	^Citation70
Glutamate metabotropic receptor 5 (GRM5, previous symbol- mGlu5)	The C-terminus contains a novel NLS between amino acid residues 852 and 876.	Primary rat striatal neurons	^Citation87

Joyal JS, Nim S, Zhu T, Sitaras N, Rivera JC, Shao Z, Sapieha P, Hamel D, Sanchez M, Zaniolo K, et al. Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis. Nat Med 2014; 20:1165-73; PMID:25216639; http://dx.doi.org/10.1038/nm.3669

 PubMed Web of Science ®Google Scholar

Di Benedetto A, Sun L, Zambonin CG, Tamma R, Nico B, Calvano CD, et al. Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor. Proc Natl Acad Sci U S A 2014; 111:16502-7; PMID:25378700; http://dx.doi.org/10.1073/pnas.1419349111

 PubMed Web of Science ®Google Scholar

Mosca TJ, Schwarz TL. The nuclear import of Frizzled2-C by Importins-beta11 and alpha2 promotes postsynaptic development. Nat Neurosci 2010; 13:935-43; PMID:20601947; http://dx.doi.org/10.1038/nn.2593

 PubMed Web of Science ®Google Scholar

Bhosle VK, Rivera JC, Zhou TE, Omri S, Sanchez M, Hamel D, Zhu T, Rouget R, Rabea AA, Hou X, et al. Nuclear localization of platelet-activating factor receptor controls retinal neovascularization. Cell Discov 2016; 2:16017; PMID:27462464; http://dx.doi.org/10.1038/celldisc.2016.17

 PubMedGoogle Scholar

Wright CD, Wu SC, Dahl EF, Sazama AJ, O'Connell TD. Nuclear localization drives alpha1-adrenergic receptor oligomerization and signaling in cardiac myocytes. Cell Signal 2012; 24:794-802; PMID:22120526; http://dx.doi.org/10.1016/j.cellsig.2011.11.014

 PubMed Web of Science ®Google Scholar

Lu D, Yang H, Shaw G, Raizada MK. Angiotensin II-induced nuclear targeting of the angiotensin type 1 (AT1) receptor in brain neurons. Endocrinology 1998; 139:365-75; PMID:9421435

 PubMed Web of Science ®Google Scholar

Bkaily G, Sleiman S, Stephan J, Asselin C, Choufani S, Kamal M, Jacques D, Gobeil F Jr, D'Orléans-Juste P. Angiotensin II AT1 receptor internalization, translocation and de novo synthesis modulate cytosolic and nuclear calcium in human vascular smooth muscle cells. Can J Physiol Pharmacol 2003; 81:274-87; PMID:12733826; http://dx.doi.org/10.1139/y03-007

 PubMed Web of Science ®Google Scholar

Lee DK, Lanca AJ, Cheng R, Nguyen T, Ji XD, Gobeil F, Jr, Chemtob S, George SR, O'Dowd BF. Agonist-independent nuclear localization of the Apelin, angiotensin AT1, and bradykinin B2 receptors. J Biol Chem 2004; 279:7901-8; PMID:14645236; http://dx.doi.org/10.1074/jbc.M306377200

 PubMed Web of Science ®Google Scholar

Savard M, Barbaz D, Belanger S, Muller-Esterl W, Bkaily G, D'Orleans-Juste P, Coté J, Bovenzi V, Gobeil F Jr. Expression of endogenous nuclear bradykinin B2 receptors mediating signaling in immediate early gene activation. J Cell Physiol 2008; 216:234-44; PMID:18264983; http://dx.doi.org/10.1002/jcp.21398

 PubMed Web of Science ®Google Scholar

Favre N, Camps M, Arod C, Chabert C, Rommel C, Pasquali C. Chemokine receptor CCR2 undergoes transportin1-dependent nuclear translocation. Proteomics 2008; 8:4560-76; PMID:18846510; http://dx.doi.org/10.1002/pmic.200800211

 PubMed Web of Science ®Google Scholar

Don-Salu-Hewage AS, Chan SY, McAndrews KM, Chetram MA, Dawson MR, Bethea DA, Hinton CV. Cysteine (C)-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells. PLoS One 2013; 8:e57194; PMID:23468933; http://dx.doi.org/10.1371/journal.pone.0057194

 PubMed Web of Science ®Google Scholar

Nielsen CK, Campbell JI, Ohd JF, Morgelin M, Riesbeck K, Landberg G, Sjölander A. A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells. Cancer Res 2005; 65:732-42; PMID:15705869

 PubMed Web of Science ®Google Scholar

Bkaily G, Choufani S, Hassan G, El-Bizri N, Jacques D, D'Orleans-Juste P. Presence of functional endothelin-1 receptors in nuclear membranes of human aortic vascular smooth muscle cells. J Cardiovasc Pharmacol 2000; 36:S414-7; PMID:11078437; http://dx.doi.org/10.1097/00005344-200036051-00121

 PubMed Web of Science ®Google Scholar

Jacques D, Descorbeth M, Abdel-Samad D, Provost C, Perreault C, Jules F. The distribution and density of ET-1 and its receptors are different in human right and left ventricular endocardial endothelial cells. Peptides 2005; 26:1427-35; PMID:16042982; http://dx.doi.org/10.1016/j.peptides.2005.03.048

 PubMed Web of Science ®Google Scholar

Cattaneo F, Parisi M, Fioretti T, Sarnataro D, Esposito G, Ammendola R. Nuclear localization of Formyl-Peptide Receptor 2 in human cancer cells. Arch Biochem Biophys 2016; 603:10-9; PMID:27177968; http://dx.doi.org/10.1016/j.abb.2016.05.006

 PubMed Web of Science ®Google Scholar

Mathew D, Ataman B, Chen J, Zhang Y, Cumberledge S, Budnik V. Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2. Science 2005; 310:1344-7; PMID:16311339; http://dx.doi.org/10.1126/science.1117051

 PubMed Web of Science ®Google Scholar

Gobeil F, Jr., Bernier SG, Vazquez-Tello A, Brault S, Beauchamp MH, Quiniou C, Marrache AM, Checchin D, Sennlaub F, Hou X, et al. Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J Biol Chem 2003; 278:38875-83; PMID:12847111; http://dx.doi.org/10.1074/jbc.M212481200

 PubMed Web of Science ®Google Scholar

Waters CM, Saatian B, Moughal NA, Zhao Y, Tigyi G, Natarajan V, Pyne S, Pyne NJ. Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA1) in mammalian cells. Biochem J 2006; 398:55-62; PMID:16716145; http://dx.doi.org/10.1042/BJ20060155

 PubMed Web of Science ®Google Scholar

Doufexis M, Storr HL, King PJ, Clark AJ. Interaction of the melanocortin 2 receptor with nucleoporin 50: evidence for a novel pathway between a G-protein-coupled receptor and the nucleus. FASEB J 2007; 21:4095-100; PMID:17625072; http://dx.doi.org/10.1096/fj.06-7927com

 PubMed Web of Science ®Google Scholar

Pickard BW, Hodsman AB, Fraher LJ, Watson PH. Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1 and beta. Endocrinology 2006; 147:3326-32; PMID:16574786; http://dx.doi.org/10.1210/en.2005-1408

 PubMed Web of Science ®Google Scholar

Marrache AM, Gobeil F, Jr, Bernier SG, Stankova J, Rola-Pleszczynski M, Choufani S, Bkaily G, Bourdeau A, Sirois MG, Vazquez-Tello A, et al. Proinflammatory gene induction by platelet-activating factor mediated via its cognate nuclear receptor. J Immunol 2002; 169:6474-81; PMID:12444157; http://dx.doi.org/10.4049/jimmunol.169.11.6474

 PubMed Web of Science ®Google Scholar

Valdehita A, Bajo AM, Fernandez-Martinez AB, Arenas MI, Vacas E, Valenzuela P, Ruíz-Villaespesa A, Prieto JC, Carmena MJ. Nuclear localization of vasoactive intestinal peptide (VIP) receptors in human breast cancer. Peptides 2010; 31:2035-45; PMID:20691743; http://dx.doi.org/10.1016/j.peptides.2010.07.024

 PubMed Web of Science ®Google Scholar

Sergin I, Jong Y-JI, Harmon SK, Kumar V, O'Malley KL. Sequences within the C-terminus of the metabotropic glutamate receptor, mGluR5, are responsible for inner nuclear membrane localization. J Biol Chem 2017; pii: jbc.M116.757724; PMID:28096465; http://dx.doi.org/10.1074/jbc.M116.757724

 Google Scholar