Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6
Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6
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DOI：
10.1126/scisignal.aat9519
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发表时间：
2019-11
影响因子：
7.3
通讯作者：
Ryota Sada;Hirokazu Kimura;Y. Fukata;M. Fukata;Hideki Yamamoto;A. Kikuchi
中科院分区：
文献类型：
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作者：
Ryota Sada;Hirokazu Kimura;Y. Fukata;M. Fukata;Hideki Yamamoto;A. Kikuchi
DKK 1刺激其受体CKAP 4和LRP 6的去棕榈酰化，导致它们从脂筏移动。Dickkopf 1（DKK 1）通过促进Wnt辅助受体LRP 6的内化来抑制Wnt信号传导。DKK 1还与细胞表面受体CKAP 4结合，并通过激酶PI 3 K和AKT刺激信号传导，从而促进细胞增殖。使用培养的癌细胞系，Sada等人发现CKAP 4和LRP 6被棕榈酰化并定位于脂筏。CKAP 4的棕榈酰化是DKK 1刺激细胞增殖所必需的。DKK 1刺激两种受体的去棕榈酰化，使它们以PI 3 K和AKT依赖的方式移出脂筏，并从脂筏中去除CKAP 4使细胞对DKK 1脱敏。DKK 1、CKAP 4和LRP 6形成三元复合物，并且LRP 6增强DKK 1和CKAP 4下游的PI 3 K-AKT活化。因此，DKK 1受体的动态棕榈酰化在介导对DKK 1的反应和控制细胞对DKK 1的敏感性方面起着重要作用。Dickkopf 1（DKK 1）最初被鉴定为Wnt信号传导的拮抗剂，其结合并诱导网格蛋白介导的Wnt辅助受体低密度脂蛋白受体相关蛋白5和6（LRP 5/6）的内吞作用。DKK 1还与细胞因子相关蛋白4（CKAP 4）结合，CKAP 4最初被鉴定为内质网（ER）蛋白，但也在质膜上作为各种配体的受体发挥作用。DKK 1-CKAP 4通路在几种人类癌症中被激活，并通过激活激酶PI 3 K和AKT的信号传导来促进细胞增殖。我们发现CKAP 4和LRP 6主要以棕榈酰化依赖的方式定位于质膜的耐洗涤剂膜（DRM）部分，并且CKAP 4的棕榈酰化是促进细胞增殖所必需的。DKK 1通过酰基蛋白硫酯酶（APT）诱导CKAP 4和LRP 6的脱棕榈酰化，导致其易位到非DRM组分。此外，两种受体的DKK 1依赖性脱棕榈酰化需要PI 3 K-AKT途径的激活。DKK 1同时结合CKAP 4和LRP 6，导致形成三元复合物。LRP 5/6敲低通过CKAP 4降低DKK 1依赖的AKT活化和癌细胞增殖，而CKAP 4敲低不影响DKK 1依赖的通过LRP 5/6抑制Wnt信号传导。这些结果表明CKAP 4和LRP 6的棕榈酰化状态在其信号传导中起重要作用，并且LRP 5/6增强DKK 1-CKAP 4信号传导。
DKK1 stimulates depalmitoylation of its receptors CKAP4 and LRP6, causing their movement from lipid rafts. DKK1 promotes receptor depalmitoylation Dickkopf1 (DKK1) inhibits Wnt signaling by promoting internalization of the Wnt coreceptor LRP6. DKK1 also binds to the cell surface receptor CKAP4 and stimulates signaling through the kinases PI3K and AKT, which promotes cell proliferation. Using cultured cancer cell lines, Sada et al. found that CKAP4 and LRP6 were palmitoylated and localized to lipid rafts. Palmitoylation of CKAP4 was required for DKK1-stimulated cell proliferation. DKK1 stimulated depalmitoylation of both receptors, causing them to move out of lipid rafts in a PI3K- and AKT-dependent manner, and removal of CKAP4 from lipid rafts desensitized cells to DKK1. DKK1, CKAP4, and LRP6 formed a ternary complex, and LRP6 enhanced PI3K-AKT activation downstream of DKK1 and CKAP4. Thus, dynamic palmitoylation of DKK1 receptors plays an important role in both mediating the response to DKK1 and in controlling the sensitivity of cells to DKK1. 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.