title: RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling.
abstract: R-spondins (RSPOs) and their receptor leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) play pleiotropic roles in normal and cancer development as well as the survival of adult stem cells through potentiation of Wnt signaling. Current evidence indicates that RSPO-LGR4 functions to elevate levels of Wnt receptors through direct inhibition of two membrane-bound E3 ligases (RNF43 and ZNRF3), which otherwise ubiquitinate Wnt receptors for degradation. Whether RSPO-LGR4 is coupled to intracellular signaling proteins to regulate Wnt pathways remains unknown. We identified the intracellular scaffold protein IQ motif containing GTPase-activating protein 1 (IQGAP1) as an LGR4-interacting protein that mediates RSPO-LGR4's interaction with the Wnt signalosome. IQGAP1 binds to and modulates the activities of a plethora of signaling molecules, including MAP kinases, Rho GTPases, and components of the Wnt signaling pathways. Interaction of LGR4 with IQGAP1 brings RSPO-LGR4 to the Wnt signaling complex through enhanced IQGAP1-DVL interaction following RSPO stimulation. In this configuration, RSPO-LGR4-IQGAP1 potentiates β-catenin-dependent signaling by promoting MEK1/2-medidated phosphorylation of LRP5/6 as well as β-catenin-independent signaling through regulation of actin dynamics. Overall, these findings reveal that RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex, leading to potent and robust potentiation of both the canonical and noncanonical pathways of Wnt signaling.
authors.affiliation: Brown Foundation Institute of Molecular Medicine and Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX 77030.
authors.forename: Kendra S
authors.initials: KS
authors.lastname: Carmon
authors.forename: Xing
authors.initials: X
authors.lastname: Gong
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.forename: Anthony
authors.initials: A
authors.lastname: Thomas
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D019699:Thrombospondins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D000098907:R-Spondins
chemical_list: D000199:Actins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D020929:Mitogen-Activated Protein Kinase Kinases; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; D044767:Ubiquitin-Protein Ligases; D051176:beta Catenin; D020703:ras GTPase-Activating Proteins; C101203:IQ motif containing GTPase activating protein 1; C411562:LGR4 protein, human; C555475:LRP6 protein, human; C503243:RSPO1 protein, human; D000098907:R-Spondins; C572950:ZNRF3 protein, human
keywords: adhesion; cell signaling; migration; receptor activation