Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling
Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling
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DOI：
10.1242/jcs.091876
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发表时间：
2012-01-15
影响因子：
4
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
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作者：
Sakane, Hiroshi;Yamamoto, Hideki;Kikuchi, Akira
Glypicans是硫酸肝素原聚糖（HSPGs）的成员，参与多种生长因子信号传导机制。尽管HSPGs影响Wnt信号的β -连环蛋白依赖性和非依赖性通路，但它们如何调节不同的Wnt通路尚不清楚。有研究表明，β -连环蛋白依赖途径是通过脂筏微域的受体内吞作用启动的，而独立途径是通过非脂筏微域的受体内吞作用激活的。在这里，有证据表明glypican-4 （GPC4）定位于两个膜微域，并且定位影响其调节不同Wnt通路的能力。GPC4结合Wnt3a和Wnt5a，分别激活β -连环蛋白依赖性和非依赖性通路，并与细胞表面的wnt共定位。Wnt3a共受体之一的LRP6存在于脂筏微域，而Wnt5a共受体之一的Ror2则定位于非脂筏微域。表达GPC4可增强wnt3a依赖性β -catenin通路和wnt5a依赖性β -catenin非依赖性通路，而敲低GPC4可抑制这两种通路。一个仅定位于非脂质筏微结构域的GPC4突变体抑制了β -catenin依赖性途径，但增强了β -catenin非依赖性途径。这些结果表明，GPC4将Wnt3a和Wnt5a浓缩到不同膜微域的特异性受体附近，从而调节不同的Wnt信号传导。
Glypicans are members of the heparan sulfate protcoglycans (HSPGs) and are involved in various growth factor signaling mechanisms. Although HSPGs affect the beta-catenin-dependent and -independent pathways of Wnt signaling, how they regulate distinct Wnt pathways is not clear. It has been suggested that the beta-catenin-dependent pathway is initiated through receptor endocytosis in lipid raft microdomains and the independent pathway is activated through receptor endocytosis in non-lipid raft microdomains. Here, evidence is presented that glypican-4 (GPC4) is localized to both membrane microdomains and that the localization affects its ability to regulate distinct Wnt pathways. GPC4 bound to Wnt3a and Wnt5a, which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with Wnts on the cell surface. LRP6, one of Wnt3a coreceptors, was present in lipid raft microdomains, whereas Ror2, one of Wnt5a coreceptors, was localized to non-lipid raft microdomains. Expression of GPC4 enhanced the Wnt3a-dependent beta-catenin pathway and the Wnt5a-dependent beta-catenin-independent pathway, and knockdown of GPC4 suppressed both pathways. A GPC4 mutant that was localized to only non-lipid raft microdomains inhibited the beta-catenin-dependent pathway but enhanced the beta-catenin-independent pathway. These results suggest that GPC4 concentrates Wnt3a and Wnt5a to the vicinity of their specific receptors in different membrane microdomains, thereby regulating distinct Wnt signaling.