G protein-coupled receptors in stem cell maintenance and somatic reprogramming to pluripotent or cancer stem cells

  • Choi, Hye Yeon (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Saha, Subbroto Kumar (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Kim, Kyeongseok (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Kim, Sangsu (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Yang, Gwang-Mo (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Kim, BongWoo (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Kim, Jin-Hoi (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Cho, Ssang-Goo (Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University)
  • Received : 2014.11.18
  • Published : 2015.02.28


G protein-coupled receptors (GPCRs) are a large class of transmembrane receptors categorized into five distinct families: rhodopsin, secretin, adhesion, glutamate, and frizzled. They bind and regulate 80% of all hormones and account for 20-50% of the pharmaceuticals currently on the market. Hundreds of GPCRs integrate and coordinate the functions of individual cells, mediating signaling between various organs. GPCRs are crucial players in tumor progression, adipogenesis, and inflammation. Several studies have also confirmed their central roles in embryonic development and stem cell maintenance. Recently, GPCRs have emerged as key players in the regulation of cell survival, proliferation, migration, and self-renewal in pluripotent (PSCs) and cancer stem cells (CSCs). Our study and other reports have revealed that the expression of many GPCRs is modulated during the generation of induced PSCs (iPSCs) or CSCs as well as during CSC sphere formation. These GPCRs may have crucial roles in the regulation of self-renewal and other biological properties of iPSCs and CSCs. This review addresses the current understanding of the role of GPCRs in stem cell maintenance and somatic reprogramming to PSCs or CSCs.


Supported by : National Research Foundation (NRF)


  1. Russ AP, Wattler S, Colledge WH et al (2000) Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95-99
  2. Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676
  3. Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920
  4. Clarke MF and Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124, 1111-1115
  5. Dirks PB (2006) Cancer: stem cells and brain tumours. Nature 444, 687-688
  6. Pierce KL, Premont RT and Lefkowitz RJ (2002) Seventransmembrane receptors. Nat Rev Mol Cell Biol 3, 639-650
  7. Dorsam RT and Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7, 79-94
  8. O'Hayre M, Degese MS and Gutkind JS (2014) Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol 27, 126-135
  9. Overington JP, Al-Lazikani B and Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5, 993-996
  10. Takeda S, Kadowaki S, Haga T, Takaesu H and Mitaku S (2002) Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett 520, 97-101
  11. Fredriksson R, Lagerstrom MC, Lundin LG and Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63, 1256-1272
  12. Gloriam DE, Fredriksson R and Schioth HB (2007) The G protein-coupled receptor subset of the rat genome. BMC Genomics 8, 338
  13. Taussig R, Iniguez-Lluhi JA and Gilman AG (1993) Inhibition of adenylyl cyclase by Gi alpha. Science 261, 218-221
  14. Hubbard KB and Hepler JR (2006) Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins. Cell Signal 18, 135-150
  15. Sassone-Corsi P (2012) The cyclic AMP pathway. Cold Spring Harb Perspect Biol 4, 1-3
  16. Gutkind JS (1998) The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. J Biol Chem 273, 1839-1842
  17. Han D, Kim HJ, Choi HY et al (2014) 3,2'-Dihydroxyflavone-treated Pluripotent Stem Cells Show Enhanced Proliferation, Pluripotency Markers Expression, and Neuroprotective Properties. Cell Transplant [Epub ahead of print].
  18. Jeon K, Oh HJ, Lim H et al (2012) Self-renewal of embryonic stem cells through culture on nanopattern polydimethylsiloxane substrate. Biomaterials 33, 5206-5220
  19. Jeon K, Lim H, Kim JH et al (2012) Bax inhibitor-1 enhances survival and neuronal differentiation of embryonic stem cells via differential regulation of mitogen-activated protein kinases activities. Biochim Biophys Acta 1823, 2190-2200
  20. Nakamura K, Salomonis N, Tomoda K, Yamanaka S and Conklin BR (2009) G(i)-coupled GPCR signaling controls the formation and organization of human pluripotent colonies. PLoS One 4, e7780
  21. Layden BT, Newman M, Chen F, Fisher A and Lowe WL Jr (2010) G protein coupled receptors in embryonic stem cells: a role for Gs-alpha signaling. PLoS One 5, e9105
  22. Callihan P, Mumaw J, Machacek DW, Stice SL and Hooks SB (2011) Regulation of stem cell pluripotency and differentiation by G protein coupled receptors. Pharmacol Ther 129, 290-306
  23. Melchiorri D, Cappuccio I, Ciceroni C et al (2007) Metabotropic glutamate receptors in stem/progenitor cells. Neuropharmacology 53, 473-480
  24. Cappuccio I, Spinsanti P, Porcellini A et al (2005) Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells. Neuropharmacology 49 Suppl 1, 196-205
  25. Cappuccio I, Verani R, Spinsanti P et al (2006) Contextdependent regulation of embryonic stem cell differentiation by mGlu4 metabotropic glutamate receptors. Neuropharmacology 51, 606-611
  26. Ciceroni C, Mosillo P, Mastrantoni E et al (2010) mGLU3 metabotropic glutamate receptors modulate the differentiation of SVZ-derived neural stem cells towards the astrocytic lineage. Glia 58, 813-822
  27. Schwirtlich M, Emri Z, Antal K, Mate Z, Katarova Z and Szabo G (2010) GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca(2+). FASEB J 24, 1218-1228
  28. Teng L, Tang YB, Sun F et al (2013) Non-neuronal release of gamma-aminobutyric Acid by embryonic pluripotent stem cells. Stem Cells Dev 22, 2944-2953
  29. Bachelerie F, Ben-Baruch A, Burkhardt AM et al (2014) International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66, 1-79
  30. Southgate TD, McGinn OJ, Castro FV et al (2010) CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. PLoS One 5, e9982
  31. Carbajal KS, Schaumburg C, Strieter R, Kane J and Lane TE (2010) Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc Natl Acad Sci U S A 107, 11068-11073
  32. Williams JL, Patel JR, Daniels BP and Klein RS (2014) Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system. J Exp Med 211, 791-799
  33. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4, 873-884
  34. Brown AJ (2007) Novel cannabinoid receptors. Br J Pharmacol 152, 567-575
  35. Jiang S, Fu Y, Williams J et al (2007) Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells. PLoS One 2, e641
  36. Rossi F, Bernardo ME, Bellini G et al (2013) The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties. PLoS One 8, e80022
  37. Galve-Roperh I, Chiurchiu V, Diaz-Alonso J, Bari M, Guzman M and Maccarrone M (2013) Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res 52, 633-650
  38. Gowran A, McKayed K and Campbell VA (2013) The cannabinoid receptor type 1 is essential for mesenchymal stem cell survival and differentiation: implications for bone health. Stem Cells Int 2013, 796715
  39. McIntyre TM, Pontsler AV, Silva AR et al (2003) Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist. Proc Natl Acad Sci U S A 100, 131-136
  40. Rodgers A, Mormeneo D, Long JS, Delgado A, Pyne NJ and Pyne S (2009) Sphingosine 1-phosphate regulation of extracellular signal-regulated kinase-1/2 in embryonic stem cells. Stem Cells Dev 18, 1319-1330
  41. Schuck S, Soloaga A, Schratt G, Arthur JS and Nordheim A (2003) The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells. BMC Mol Biol 4, 6
  42. Pebay A, Wong RC, Pitson SM et al (2005) Essential roles of sphingosine-1-phosphate and platelet-derived growth factor in the maintenance of human embryonic stem cells. Stem Cells 23, 1541-1548
  43. Whetton AD, Lu Y, Pierce A, Carney L and Spooncer E (2003) Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1. Blood 102, 2798-2802
  44. Jaganathan BG, Ruester B, Dressel L et al (2007) Rho inhibition induces migration of mesenchymal stromal cells. Stem Cells 25, 1966-1974
  45. Donati C, Cencetti F, Nincheri P et al (2007) Sphingosine 1-phosphate mediates proliferation and survival of mesoangioblasts. Stem Cells 25, 1713-1719
  46. Song M, Paul S, Lim H, Dayem AA and Cho SG (2012) Induced pluripotent stem cell research: a revolutionary approach to face the challenges in drug screening. Arch Pharm Res 35, 245-260
  47. Xu XX, Zhang LH and Xie X (2014) Somatostatin receptor type 2 contributes to the self-renewal of murine embryonic stem cells. Acta Pharmacol Sin 35, 1023-1030
  48. Schioth HB, Nordstrom KJ and Fredriksson R (2010) The adhesion GPCRs; gene repertoire, phylogeny and evolution. Adv Exp Med Biol 706, 1-13
  49. Yona S, Lin HH, Siu WO, Gordon S and Stacey M (2008) Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci 33, 491-500
  50. Bai Y, Du L, Shen L, Zhang Y and Zhang L (2009) GPR56 is highly expressed in neural stem cells but downregulated during differentiation. Neuroreport 20, 918-922
  51. Formstone CJ and Little PF (2001) The flamingo-related mouse Celsr family (Celsr1-3) genes exhibit distinct patterns of expression during embryonic development. Mech Dev 109, 91-94
  52. Seandel M, Falciatori I, Shmelkov SV, Kim J, James D and Rafii S (2008) Niche players: spermatogonial progenitors marked by GPR125. Cell Cycle 7, 135-140
  53. Foord SM, Bonner TI, Neubig RR et al (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev 57, 279-288
  54. Wang HY, Liu T and Malbon CC (2006) Structure-function analysis of Frizzleds. Cell Signal 18, 934-941
  55. Nusse R (2008) Wnt signaling and stem cell control. Cell Res 18, 523-527
  56. Cai L, Ye Z, Zhou BY, Mali P, Zhou C and Cheng L (2007) Promoting human embryonic stem cell renewal or differentiation by modulating Wnt signal and culture conditions. Cell Res 17, 62-72
  57. Walsh J and Andrews PW (2003) Expression of Wnt and Notch pathway genes in a pluripotent human embryonal carcinoma cell line and embryonic stem cell. APMIS 111, 197-210; discussion 210-191
  58. Ding VM, Ling L, Natarajan S, Yap MG, Cool SM and Choo AB (2010) FGF-2 modulates Wnt signaling in undifferentiated hESC and iPS cells through activated PI3-K/GSK3beta signaling. J Cell Physiol 225, 417-428
  59. Melchior K, Weiss J, Zaehres H et al (2008) The WNT receptor FZD7 contributes to self-renewal signaling of human embryonic stem cells. Biol Chem 389, 897-903
  60. Tam WL, Lim CY, Han J et al (2008) T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways. Stem Cells 26, 2019-2031
  61. Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H and Doble BW (2011) beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell 8, 214-227
  62. Lyashenko N, Winter M, Migliorini D, Biechele T, Moon RT and Hartmann C (2011) Differential requirement for the dual functions of beta-catenin in embryonic stem cell self-renewal and germ layer formation. Nat Cell Biol 13, 753-761
  63. Yi F, Pereira L, Hoffman JA et al (2011) Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol 13, 762-770
  64. Miki T, Yasuda SY and Kahn M (2011) Wnt/beta-catenin signaling in embryonic stem cell self-renewal and somatic cell reprogramming. Stem Cell Rev 7, 836-846
  65. Afroze S, Meng F, Jensen K et al (2013) The physiological roles of secretin and its receptor. Ann Transl Med 1, 29
  66. Dickson L and Finlayson K (2009) VPAC and PAC receptors: From ligands to function. Pharmacol Ther 121, 294-316
  67. Lee CH, Kim JH, Lee HJ et al (2011) The generation of iPS cells using non-viral magnetic nanoparticle based transfection. Biomaterials 32, 6683-6691
  68. Yang W, Wei W, Shi C et al (2009) Pluripotin combined with leukemia inhibitory factor greatly promotes the derivation of embryonic stem cell lines from refractory strains. Stem Cells 27, 383-389
  69. Maherali N and Hochedlinger K (2008) Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3, 595-605
  70. Teng HF, Kuo YL, Loo MR et al (2010) Valproic acid enhances Oct4 promoter activity in myogenic cells. J Cell Biochem 110, 995-1004
  71. Spinsanti P, De Vita T, Di Castro S et al (2006) Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. J Neurochem 99, 299-307
  72. Sarichelou I, Cappuccio I, Ferranti F et al (2008) Metabotropic glutamate receptors regulate differentiation of embryonic stem cells into GABAergic neurons. Cell Death Differ 15, 700-707
  73. Todorova MG, Fuentes E, Soria B, Nadal A and Quesada I (2009) Lysophosphatidic acid induces Ca2+ mobilization and c-Myc expression in mouse embryonic stem cells via the phospholipase C pathway. Cell Signal 21, 523-528
  74. Seandel M, James D, Shmelkov SV et al (2007) Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449, 346-350
  75. Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW and St Croix B (2001) Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res 61, 6649-6655
  76. Marson A, Foreman R, Chevalier B et al (2008) Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3, 132-135
  77. Zhang P, Chang WH, Fong B et al (2014) Regulation of induced pluripotent stem (iPS) cell induction by Wnt/beta-catenin signaling. J Biol Chem 289, 9221-9232
  78. Bonnet D and Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737
  79. Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G et al (2007) Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20, 474-481
  80. Prevarskaya N, Skryma R and Shuba Y (2011) Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer 11, 609-618
  81. Dean M (2006) Cancer stem cells: redefining the paradigm of cancer treatment strategies. Mol Interv 6, 140-148
  82. Hernandez L, Magalhaes MA, Coniglio SJ, Condeelis JS and Segall JE (2011) Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis. Breast Cancer Res 13, R128
  83. Wu X, Lee VC, Chevalier E and Hwang ST (2009) Chemokine receptors as targets for cancer therapy. Curr Pharm Des 15, 742-757
  84. Lazennec G and Richmond A (2010) Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med 16, 133-144
  85. Ablett MP, O'Brien CS, Sims AH, Farnie G and Clarke RB (2014) A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. Oncotarget 5, 599-612
  86. Burdon T, Smith A and Savatier P (2002) Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 12, 432-438
  87. Levoye A, Balabanian K, Baleux F, Bachelerie F and Lagane B (2009) CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 113, 6085-6093
  88. Sarfaraz S, Adhami VM, Syed DN, Afaq F and Mukhtar H (2008) Cannabinoids for cancer treatment: progress and promise. Cancer Res 68, 339-342
  89. Aguado T, Carracedo A, Julien B et al (2007) Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem 282, 6854-6862
  90. Rogelsperger O, Ekmekcioglu C, Jager W et al (2009) Coexpression of the melatonin receptor 1 and nestin in human breast cancer specimens. J Pineal Res 46, 422-432
  91. Tan DX, Manchester LC, Terron MP, Flores LJ and Reiter RJ (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42, 28-42
  92. Ledur PF, Villodre ES, Paulus R, Cruz LA, Flores DG and Lenz G (2012) Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells. Purinergic Signal 8, 39-48
  93. Lonardo E, Hermann PC and Heeschen C (2010) Pancreatic cancer stem cells - update and future perspectives. Mol Oncol 4, 431-442
  94. MacDonald BT, Tamai K and He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17, 9-26
  95. Moriconi A, Cesta MC, Cervellera MN et al (2007) Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem 50, 3984-4002

Cited by

  1. Targeting glioblastoma stem cells (GSCs) with peroxisome proliferator-activated receptor gamma (PPARγ) ligands vol.68, pp.3, 2016,
  2. Blood-brain barrier-supported neurogenesis in healthy and diseased brain vol.28, pp.4, 2017,
  3. An investigation into the potential role of brain angiogenesis inhibitor protein 3 (BAI3) in the tumorigenesis of small-cell carcinoma: a review of the surrounding literature vol.37, pp.4, 2017,
  4. Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo vol.118, pp.8, 2016,
  5. Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK) vol.50, pp.11, 2017,
  6. Plasticity of Adipose Tissue-Derived Stem Cells and Regulation of Angiogenesis vol.9, pp.1664-042X, 2018,
  7. Transcriptional Landscape of PARs in Epithelial Malignancies vol.19, pp.11, 2018,
  8. Global phenotypic characterisation of human platelet lysate expanded MSCs by high-throughput flow cytometry vol.8, pp.1, 2018,
  9. Endothelial Differentiation G Protein-Coupled Receptor 5 Plays an Important Role in Induction and Maintenance of Pluripotency vol.37, pp.3, 2019,