KMC designed research studies, provided intellectual support, and edited the manuscript. Supplementary Material Supplemental data:Click here to view.(2.0M, pdf) Acknowledgments We thank IKK-gamma (phospho-Ser85) antibody the University of North Carolina Lineberger Animal Histopathology Core (NIH CA16086); the Center for Gastrointestinal Biology and Disease (NIH P30-DK34987); the Microscopy Services Laboratory; as well as Kirk McNaughton and Ashley Ezzell of the Histology Research Core. was profoundly reduced in numerous human carcinomas, including colon adenocarcinoma. Together, these results implicate as a negative regulator of intestinal MAPK signalingCinduced proliferation, particularly during regeneration and adenoma Plerixafor 8HCl (DB06809) formation. Introduction Deorphanization of GPCRs remains an active area of research, especially considering that approximately 40% of all approved drugs for humans target only a small fraction of the GPCRome (1, 2). In addition to elucidating the pharmacology of orphan GPCRs, it is crucial to characterize the anatomical locations and physiological functions of these receptors in vivo. G proteinCcoupled receptor 182 (GPR182, formerly known as G10D or adrenomedullin receptor [ADMR]) (3, 4), is usually a class A orphan GPCR with very little known about its expression, function, regulation, or pharmacology. GPR182 is usually grouped within the chemokine receptor family by phylogeny, with the atypical chemokine receptor 3 (ACKR3, formerly known as CXCR7 or RDC1) as its closest paralog, despite the two sharing a modest, less-than-30% sequence homology in mice and humans. GPR182 was previously considered Plerixafor 8HCl (DB06809) a putative receptor for the multifunctional peptide adrenomedullin (4), however, these initial findings were not consistent among laboratories (5), and Plerixafor 8HCl (DB06809) it was later shown Plerixafor 8HCl (DB06809) that adrenomedullin signals through a different GPCR complex (6). Unfortunately, the former ADMR nomenclature is sometimes still used, which leads to confusion in the field. For example, was reported to be expressed in numerous human pancreatic cancer cell lines, and knockdown of in these cells decreased xenograft tumor growth, which the authors concluded was due to a loss of adrenomedullin signaling (7, 8). Anatomical expression profiling of the GPCRome exhibited the relatively ubiquitous low expression of in most mouse tissues (9). More recently, was found to be highly expressed in developing murine and zebrafish endothelium and enriched in mammary tumor endothelium compared with normal mammary endothelium (10C12). Additionally, was identified among a group of factors that are significantly altered in a zebrafish model of myeloid leukemia (13). Thus, a significant advance of the current study is usually to map the expressional profile of using an in vivo mammalian reporter model, in which, in addition to the endothelium of numerous tissues, we observed expression within the gastrointestinal tract epithelia. The epithelium of the gastrointestinal tract is one of the most dynamic tissues in the adult body and is primarily responsible for the absorption of dietary nutrients and also for fulfilling important endocrine, immune, and protective barrier functions. To maintain its proper functions, the intestinal epithelium must undergo continuous turnover, with the entire small intestinal epithelium renewing every week in humans and in mice. This constant renewal is usually driven by an active populace of intestinal stem cells (ISCs) that are located at the base of the crypts of Lieberkhn, where they give rise to rapidly dividing daughter transit-amplifying progenitor cells that differentiate into the absorptive or secretory lineages responsible for functions of the intestine (14C17). Current views hold that 2 distinct pools of ISCs Plerixafor 8HCl (DB06809) exist in the intestinal epithelium: the crypt base columnar (CBC) ISCs, which are positioned between differentiated Paneth cells and mediate normal homeostatic renewal, and damage-resistant ISCs, which act as reserve ISCs that are activated following injury (14, 15, 17, 18). With the discovery of numerous ISC-specific markers including leucine-rich repeat made up of G proteinCcoupled receptor 5 (our understanding of both of these ISC populations has drastically expanded over the past decade (19C26). It is evident that the activity and proliferation of these ISCs must be tightly controlled by numerous signaling pathways and redundant mechanisms in order to maintain homeostasis in the dynamic gut microenvironment (14, 27). Furthermore, oncogenic mutations specifically in ISCs can drastically enhance adenoma formation in mice (20, 28). Thus, defining the factors that.