RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling
RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling
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DOI：
10.1073/pnas.1323106111
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发表时间：
2014-04-01
影响因子：
11.1
通讯作者：
Liu, Qingyun
中科院分区：
文献类型：
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作者：
Carmon, Kendra S.;Gong, Xing;Liu, Qingyun
R-spondins（RSPO）及其受体富含亮氨酸重复的G蛋白偶联受体4（LGR 4）通过增强Wnt信号传导在正常和癌症发展以及成体干细胞的存活中发挥多效性作用。目前的证据表明，RSPO-LGR 4通过直接抑制两种膜结合的E3连接酶（RNF 43和ZNRF 3）来提高Wnt受体的水平，否则它们会泛素化Wnt受体进行降解。RSPO-LGR 4是否与细胞内信号蛋白偶联以调节Wnt途径仍是未知的。我们鉴定了含有GTP酶激活蛋白1（IQGAP 1）的细胞内支架蛋白IQ基序作为介导RSPO-LGR 4与Wnt信号体相互作用的LGR 4相互作用蛋白。IQGAP 1结合并调节多种信号分子的活性，包括MAP激酶、Rho GTP酶和Wnt信号通路的组分。LGR 4与IQGAP 1的相互作用通过RSPO刺激后增强的IQGAP 1-DVL相互作用将RSPO-LGR 4带到Wnt信号传导复合物。在这种配置中，RSPO-LGR 4-IQGAP 1通过促进MEK 1/2介导的LRP 5/6磷酸化以及通过调节肌动蛋白动力学的β-连环蛋白非依赖性信号传导来增强β-连环蛋白依赖性信号传导。总体而言，这些发现表明，RSPO-LGR 4不仅诱导RNF 43/ZNRF 3的清除以增加Wnt受体水平，而且还将IQGAP 1募集到Wnt信号传导复合物中，导致Wnt信号传导的经典和非经典途径的有效和稳健增强。
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 beta-catenin-dependent signaling by promoting MEK1/2-medidated phosphorylation of LRP5/6 as well as beta-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.