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ntext of any given GPCR. Some GPCRs, such as sphingosine-1-phosphate receptor 1, exclusively couple to one G protein, whereas other GPCRs, such as lysophosphatidic acid receptors, can couple to multiple G proteins triggering diverse downstream signaling cascades. Aberrant activation of GPCR signaling triggered by high-affinity ligands leads to malignant transformation, proliferation, metastasis and drug resistance. Int. J. Mol. Sci. 2016, 17, 707 3 of 18 Int. J. Mol. Sci. 2016, 17, 707 3 of 18 2.1. GPCR-Mediated Regulation of Stem Cell Properties 2.1. GPCR-Mediated Regulation of Stem Cell Properties The role of GPCR signaling stem cell function, although undoubtedly important, has has not The role of GPCR signaling in in stem cell function, although undoubtedly important,not been been elucidated. Several lines lines of evidencesuggestive of a critical role,role,instance many of the fully fully elucidated. Several of evidence are are suggestive of a critical for for instance many of the signaling cascades activated by GPCR signaling directly regulate, or are synergistic with, pathways that regulate ESC pluripotency and differentiation. General roles for G proteins in regulating pluripotency have also been described. General roles for G proteins in regulating pluripotency have also been described. Gs signaling has PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19820119 been shown to promote proliferation and pluripotency in self-renewing and differentiating mouse ESCs. Signaling mediated by Gi proteins is demonstrated to affect the morphology and organization of human induced pluripotent stem cells . Dramatic changes in the expression levels of GPCRs in distinct stages of stem cell differentiation further implicate their involvement in stem cell function. Comprehensive qPCR analysis of more than 350 GPCR genes between three stages of in vitro neural differentiation has revealed striking differences in GPCR expression within the different cell populations. The GPCR superfamily is divided into five sub-families, including glutamate, frizzled, adhesion, rhodopsin and secretin. The specific roles of GPCRs from two of these families will be discussed in this review exemplifying GPCR-mediated regulation of normal and malignant stem cells. 2.2. Wnt-Activated Fzd Signaling The frizzled family of GPCRs is activated by the Wnt family of lipoglycoproteins. Wnt signaling plays a critical role during development and Wnt ligands are known to regulate the maintenance of numerous stem cell populations in both developing and adult organisms. Although Fzds have normal GPCR topology, their lack of sequence similarity leads to debate regarding their classification as GPCRs. Nevertheless, compelling experimental observations show that heterotrimeric G proteins play a crucial role in Wnt signaling, specifically given that Wnt signaling activation could be abrogated in human ESCs by a Gi/o protein inhibitor . Furthermore, Go has been shown to be essential for Wnt activation in Drosophila. As such, the Fzd family is listed by the International Union of Pharmacology as a novel and separate family of GPCRs termed “Class Frizzled”. Nineteen Wnt proteins serve as the primary endogenous agonists for 10 Fzd receptors encoded in the human genome. There is apparent specificity between individual Fzds and their ligands with Wnt3a-Fzd1, Wnt5a-Fzd7 and Wnt7-Fzd6 being identified as highly efficient MedChemExpress Pyrroloquinolinequinone disodium salt Wnt-Fzd pairs. Three main pathways in Wnt-activated Fzd signaling include: Fzd/Ca2+ pathway, Fzd/planar cell polarity pathway and F