Lgr4 (leucine-rich repeat G-protein coupled receptor 4), also called GPR48, is a seven-transmembrane glycoprotein receptor in the Lgr family of cell surface receptors (1, 2). While this family includes receptors for hormones such as LH, FSH, TSH, and HCG, the subfamily comprising Lgr4, Lgr5, and Lgr6 are G-protein independent mediators of the potentiating effect of R-Spondins on Wnt signaling (1-6). Lgr4 binds and forms complexes with R-Spondins, Frizzled Wnt receptors and LRP Wnt
co-receptors (5). It acts at least in part by enhancing Wnt-dependent LRP phosphorylation, internalization of LRPs, and accumulation of beta -catenin (3, 4). Mouse Lgr4 cDNA encodes 951 amino acids (aa), including a long N-terminal extracellular domain (ECD, aa 25-544) with 16-17 LRR domains that mediate ligand interaction (1). The LRR-containing ECD of mouse Lgr4 shares 93%, 97% and 90% aa sequence identity with human, rat and bovine Lgr4, respectively, and 52-53% aa identity with mouse Lgr5 and Lgr6. Rodent Lgr4 is widely expressed in both embryo and adult, with mRNA found in tissues including liver, kidney, adrenals, bone/cartilage, and heart (2, 7-9). Expression of Lgr4 mRNA in adult humans is highest in pancreas, followed by liver, heart, muscle, brain, and placenta (1). Lgr4 deletion in the mouse affects development in areas of expression, for example, inhibiting fetal liver definitive erythropoiesis, and arresting germ cell meiosis, thus blocking spermatogenesis (9, 10). Deletion of Lgr4 specifically from stem and progenitor cells in intestinal crypts induces loss of crypts due to insufficient Wnt signaling. LGR4^-/- mice show hyperactivity of innate immune responses, and are also susceptible to more severe inflammatory bowel disease induction (5, 6, 11, 12). Lgr4 may be over-expressed in carcinomas and may promote invasiveness and metastasis by down‑regulating p27^Kip1 expression (13).