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G Protein-Coupled Receptors in Stem Cell Maintenance and Somatic Reprogramming to Pluripotent Or Cancer Stem Cells

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G Protein-Coupled Receptors in Stem Cell Maintenance and Somatic Reprogramming to Pluripotent Or Cancer Stem Cells BMB Reports - Manuscript Submission Manuscript Draft Manuscript Number: BMB-14-250 Title: G protein-coupled receptors in stem cell maintenance and somatic reprogramming to pluripotent or cancer stem cells Article Type: Mini Review Keywords: G protein-coupled receptors; stem cell maintenance; somatic reprogramming; cancer stem cells; pluripotent stem cell Corresponding Author: Ssang-Goo Cho Authors: Ssang-Goo Cho1,*, Hye Yeon Choi1, Subbroto Kumar Saha1, Kyeongseok Kim1, Sangsu Kim1, Gwang-Mo Yang1, BongWoo Kim1, Jin-hoi Kim1 Institution: 1Department of Animal Biotechnology, Animal Resources Research Center, and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea, UNCORRECTED PROOF 1 G protein-coupled receptors in stem cell maintenance and somatic reprogramming to 2 pluripotent or cancer stem cells 3 4 Hye Yeon Choi, Subbroto Kumar Saha, Kyeongseok Kim, Sangsu Kim, Gwang-Mo 5 Yang, BongWoo Kim, Jin-hoi Kim, and Ssang-Goo Cho 6 7 Department of Animal Biotechnology, Animal Resources Research Center, and 8 Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, 9 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea 10 * 11 Address correspondence to Ssang-Goo Cho, Department of Animal Biotechnology and 12 Animal Resources Research Center. Konkuk University, 120 Neungdong-ro, Gwangjin- 13 gu, Seoul 143-701, Republic of Korea. Tel: 82-2-450-4207, Fax: 82-2-450-1044, E-mail: 14 [email protected] 15 16 17 18 19 1 UNCORRECTED PROOF 20 Abstract 21 The G protein-coupled receptors (GPCRs) compose the third largest gene family in the 22 human genome, representing more than 800 distinct genes and 3–5% of the human genome. 23 GPCRs are divided into five distinct families: rhodopsin, secretin, adhesion, glutamate, and 24 frizzled. They bind and regulate 80% of all hormones and account for 20–50% of the 25 pharmaceuticals on the current market. Hundreds of GPCRs integrate and coordinate the 26 functions of individual cells, mediating signaling between various organs. GPCRs are crucial 27 players in tumor progression, adipogenesis, and inflammation. Several studies have also 28 confirmed their central roles in embryonic development and stem cell maintenance. Recently, 29 GPCRs have emerged as key players in the regulation of cell survival, proliferation, 30 migration, and self-renewal in pluripotent (PSCs) and cancer stem cells (CSCs). Our study 31 and other reports have revealed that the expression of many GPCRs is modulated during the 32 generation of induced PSCs (iPSCs) or CSCs and during CSC sphere formation. These 33 GPCRs may have crucial roles in the regulation of self-renewal and other biological 34 properties of iPSCs and CSCs. This review addresses the current understanding of the role of 35 GPCRs in stem cell maintenance and somatic reprogramming to PSCs or CSCs. 36 37 38 39 40 2 UNCORRECTED PROOF 41 Introduction 42 Many tissues of the body—for example, skin, liver, and epithelium—not only repair 43 themselves but also self-renew, a property mainly found in stem cells (1). Embryonic stem 44 cells (ESCs) have an even greater potential for self-renewal and differentiation. Recently, 45 mouse and human fibroblasts were reprogrammed into pluripotent stem cells (PSCs) through 46 the introduction of a diverse set of stem cell-related transcription factors including Oct4, 47 Sox2, Klf4, and c-myc (2, 3). These induced PSCs (iPSCs) derived from somatic fibroblasts 48 had genetic, epigenetic, and developmental features that were highly similar to those of ESCs. 49 Although ESCs and iPSCs are considered unlimited cell sources for regenerative medicine, 50 techniques for maintaining undifferentiated ESC or iPSCs remain inefficient, which results in 51 inhomogeneous cell populations. 52 Tumor cells are assumed to include a population of cells responsible for the initiation of 53 tumor development and growth and the capacity to metastasize and reoccur (4) . Because of 54 their similarities with stem cells, these cells have been named cancer stem cells (CSCs). 55 CSCs have properties such as self-renewal, heterogeneity, and resistance to apoptosis. CSCs 56 likely arise from stem cells, and the transformation of normal stem cells into CSCs may be 57 due to the accumulation of genetic modifications such as mutations in oncogenes, suppressor 58 genes, and mismatch repair genes or epigenetic alterations such as abnormal methylation and 59 histone modification (5) . 60 The factors that control the regulation of cell survival, proliferation, migration, and self- 61 renewal in PSCs and CSCs are still emerging. Some evidence demonstrates the potent effects 62 of various GPCR ligands on the biology of PSCs and CSCs. G protein-coupled receptors 3 UNCORRECTED PROOF 63 (GPCRs) are a large class of transmembrane (TM) receptors that conduct extracellular signals 64 into cells by combining with guanine nucleotide-binding proteins (G proteins) and interacting 65 with a diverse set of ligands, including biogenic amines, amino acids, ions, lipids, and 66 peptides, as well as light, taste, and odor stimuli and coupling the presence of these signals to 67 such fundamental cellular responses as growth, death, movement, transcription, and 68 excitation (6) . They are by far the largest family of cell surface molecules, and they modulate 69 key physiological functions, including neurotransmission, hormone and enzyme release, 70 immune response, and blood pressure regulation. Their signaling converges on common 71 downstream effectors and modulators, such as G proteins, arrestins, and GPCR kinases/G 72 protein-coupled receptor kinases. Most GPCRs activate one or multiple Gα proteins, which 73 can be subdivided into four major families: Gαi, Gα12, Gαs, and Gαq (7) . GPCRs act more 74 as molecular regulators than on-off switches, so the engagement of different G proteins and 75 the duration of signaling may differ not only among GPCRs but also for a given GPCR 76 depending on the ligand and cellular environment (8) . Considerable evidence now exists that 77 demonstrates the important roles of various GPCRs in the regulation of the biological 78 properties of PCSs or CSCs. 79 Recently, we analyzed the expression profiles of GPCRs during somatic reprogramming to 80 iPSCs or CSCs and during CSC sphere formation (Figure 1 and Table 1). More than 106 81 GPCRs were expressed exclusively in the PCSs or CSCs, whereas expression of 22 GPCRs 82 were down-regulated during somatic reprogramming to iPSCs. Eighty-one GPCRs were 83 differentially expressed during somatic reprogramming to iPSCs, and the expression of 195 84 GPCRs was up-regulated or down-regulated during somatic reprogramming to CSCs and 85 sphere formation of CSCs. These data suggest that various GPCRs may have key roles in 4 UNCORRECTED PROOF 86 somatic reprogramming to iPSCs or CSCs and may be involved in the regulation of the 87 specific self-renewal and other biological properties of PCSs or CSCs. Recently, considerable 88 functional evidence has accumulated to support specific roles of GPCRs in somatic 89 reprogramming or transformation to iPSCs or CSCs. In the following section, we review the 90 general role of GPCR signaling pathways and the current understanding of the role of GPCRs 91 in stem cell maintenance and somatic reprogramming to PCSs or CSCs. 92 93 General role of GPCR signaling pathways 94 GPCRs bind and regulate the effects of 80% of all hormones in the body and account for 95 20–50% of the pharmaceuticals on the current market (9). Members of the GPCR superfamily 96 are structurally defined by an extracellular N-terminus, seven TM domains, and a cytosolic 97 C-terminus (10). They compose the third largest gene family in the human genome, 98 representing more than 800 distinct genes and 3–5% of the human genome. The superfamily 99 has traditionally been divided into three major families—class A/rhodopsin-like receptors, 100 class B/secretin-like receptors, and class C/glutamate-like receptors—and recent 101 bioinformatics analyses have updated the phylogenetic characterization to five distinct 102 families: glutamate, rhodopsin, adhesion, frizzled (FZD), and secretin (i.e., the GRAFS 103 classification system) (Figure 2) (11, 12). 104 GPCR stimulation triggers the activation of heterotrimeric G proteins as guanosine 105 triphosphate (GTP) replaces guanosine diphosphate on the Gα subunit, promoting its 106 dissociation from the Gβγ subunits. Both α-GTP-bound and Gβγ subunit complexes then 107 stimulate multiple downstream signaling cascades (7), including the rapid generation of 5 UNCORRECTED PROOF 108 multiple second messengers. For example, Gαs stimulates adenylyl cyclase, increasing the 109 cytosolic levels of cyclic adenosine monophosphate (cAMP), whereas Gαi inhibits adenylyl 110 cyclase and hence decreases cAMP levels (13) . Members of the Gαq family activate 111 phospholipase-Cβ, which cleaves phosphatidylinositol-4, 5-bisphosphate into diacylglycerol 112 and inositol 1,4,5-trisphosphate; the latter increases cytosolic calcium (14) . The targets of 113 these diffusible second messengers include ion channels, calcium-sensitive enzymes, and 114 kinases such as cAMP-dependent kinase, protein kinase C, cyclic guanosine monophosphate- 115 dependent kinase, and calcium-calmodulin regulated kinases. Many of these kinases 116 contribute to cancer progression and metastasis (15). 117 Although GPCRs can stimulate multiple diffusible second messenger-generating systems,
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