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Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6.
Science Signaling ( IF 7.3 ) Pub Date : 2019-11-19 , DOI: 10.1126/scisignal.aat9519
Ryota Sada 1 , Hirokazu Kimura 1 , Yuko Fukata 2, 3 , Masaki Fukata 2, 3 , Hideki Yamamoto 1 , Akira Kikuchi 1
Affiliation  

Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6 primarily localized to detergent-resistant membrane (DRM) fractions of the plasma membrane in a palmitoylation-dependent manner and that palmitoylation of CKAP4 was required for it to promote cell proliferation. DKK1 induced the depalmitoylation of both CKAP4 and LRP6 by acylprotein thioesterases (APTs), resulting in their translocation to the non-DRM fractions. Moreover, DKK1-dependent depalmitoylation of both receptors required activation of the PI3K-AKT pathway. DKK1 simultaneously bound CKAP4 and LRP6, resulting in the formation of a ternary complex. LRP5/6 knockdown decreased DKK1-dependent AKT activation and cancer cell proliferation through CKAP4, whereas CKAP4 knockdown did not affect DKK1-dependent inhibition of Wnt signaling through LRP5/6. These results indicate that the palmitoylation states of CKAP4 and LRP6 play important roles in their signaling and that LRP5/6 enhance DKK1-CKAP4 signaling.



中文翻译:

动态棕榈酰化控制DKK1受体CKAP4和LRP6的微区定位。

Dickkopf1(DKK1)最初被认为是Wnt信号的拮抗剂,与Wnt核心受体低密度脂蛋白受体相关蛋白5和6(LRP5 / 6)结合并诱导网格蛋白介导的内吞作用。DKK1还与细胞骨架相关蛋白4(CKAP4)结合,该蛋白最初被鉴定为内质网(ER)蛋白,但在质膜上也起着各种配体的受体的作用。DKK1-CKAP4途径在几种人类癌症中被激活,并通过激活激酶PI3K和AKT的信号传导来促进细胞增殖。我们发现,CKAP4和LRP6都以棕榈酰化依赖性方式主要定位于质膜的耐去污剂膜(DRM)部分,并且CKAP4需要棕榈酰化才能促进细胞增殖。DKK1通过酰基蛋白硫酯酶(APT)诱导CKAP4和LRP6的去棕榈酸酯化,导致它们易位至非DR​​M组分。此外,两种受体的依赖DKK1的去棕榈酰化都需要激活PI3K-AKT途径。DKK1同时结合CKAP4和LRP6,导致三元复合物的形成。LRP5 / 6敲低降低了通过CKAP4依赖DKK1的AKT激活和癌细胞的增殖,而CKAP4敲低并不影响DKK1依赖的通过LRP5 / 6抑制Wnt信号。这些结果表明CKAP4和LRP6的棕榈酰化状态在它们的信号传导中起重要作用,并且LRP5 / 6增强了DKK1-CKAP4信号传导。两种受体的DKK1依赖性去棕榈酰化都需要激活PI3K-AKT途径。DKK1同时结合CKAP4和LRP6,导致三元复合物的形成。LRP5 / 6敲低降低了通过CKAP4依赖DKK1的AKT激活和癌细胞的增殖,而CKAP4敲低并不影响DKK1依赖的通过LRP5 / 6抑制Wnt信号。这些结果表明CKAP4和LRP6的棕榈酰化状态在它们的信号传导中起重要作用,并且LRP5 / 6增强了DKK1-CKAP4信号传导。两种受体的依赖DKK1的去棕榈酰化都需要激活PI3K-AKT途径。DKK1同时结合CKAP4和LRP6,导致三元复合物的形成。LRP5 / 6敲低降低了通过CKAP4依赖DKK1的AKT活化和癌细胞增殖,而CKAP4敲低并不影响DKK1依赖的通过LRP5 / 6抑制Wnt信号转导。这些结果表明CKAP4和LRP6的棕榈酰化状态在它们的信号传导中起重要作用,并且LRP5 / 6增强了DKK1-CKAP4信号传导。而CKAP4敲低并不影响DKK1依赖的通过LRP5 / 6抑制Wnt信号传导。这些结果表明CKAP4和LRP6的棕榈酰化状态在它们的信号传导中起重要作用,并且LRP5 / 6增强了DKK1-CKAP4信号传导。而CKAP4敲低并不影响DKK1依赖的通过LRP5 / 6抑制Wnt信号传导。这些结果表明CKAP4和LRP6的棕榈酰化状态在它们的信号传导中起重要作用,并且LRP5 / 6增强了DKK1-CKAP4信号传导。

更新日期:2019-11-20
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