Wnt/ $\beta$$\beta$beta\beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
Wnt/β-连环蛋白信号通路、疾病与新兴治疗策略

Since the initial discovery of the first member of the Wnt family 35 years ago (Nusse and Varmus, 1982), interest in Wnt signaling has steadily risen. In fields ranging from cancer and development to early animal evolution, Wnt signaling has emerged as a fundamental growth control pathway. Details about the mechanisms of Wnt signaling have been revealed, including structural information on the main molecular players. In this review, we will present an update (Clevers and Nusse, 2012) on recent insights into Wnt signaling in various contexts, during normal physiology as well as in disease.
自 35 年前 Wnt 家族首个成员被发现以来（Nusse 与 Varmus，1982 年），学界对 Wnt 信号通路的关注持续升温。该通路已发展成为从癌症研究、胚胎发育到早期动物进化等多个领域的核心生长调控机制。随着研究的深入，科学家们不仅揭示了 Wnt 信号传导的具体作用机制，还获得了关键蛋白的结构信息。本文综述将基于 Clevers 和 Nusse（2012 年）的研究，系统阐述该通路在正常生理状态及疾病条件下的最新研究进展。

Wnt signaling represents one of a handful of pathways, including Notch-Delta, Hedgehog, transforming growth factor $\beta$$\beta$beta\beta (TGF- $\beta$$\beta$beta\beta )/ bone morphogenetic protein (BMP) and Hippo, which are all implicated in developmental processes. Each of these signaling pathways is conserved in evolution and widespread in its activity; it could be asked what is unique about the Wnt system compared to others? What are the effects of Wnt signals on cells and why is this pathway so ubiquitously active in growing tissues? Fundamentally, Wnts are growth stimulatory factors, leading to cell proliferation (Niehrs and Acebron, 2012). In doing so, Wnt signals impact the cell cycle at various points. Compared to other growth factors, a distinctive aspect of Wnt signaling is the ability to giving shape to growing tissues while inducing cells to proliferate, acting in the process as directional growth factors (Goldstein et al., 2006; Huang and Niehrs, 2014; Schneider et al., 2015; Kitajima et al., 2013; Loh et al., 2016). Wht signals can instruct new cells to become allocated in a way such that organized body plans rather than amorphous structures are generated (Huang and Niehrs, 2014; Wu et al., 2013; Habib et al., 2013). This morphogenetic outcome of Wnt signaling is mediated by a multitude of signal transduction steps that can be activated by Wnt, resulting in changes in gene expression but also in effects on the cytoskeleton and the mitotic spindle (Sawa, 2012). Moreover, Whts employ receptors of different classes, generating a panoply of combinatorial Wnt signaling critical for
Wnt 信号通路是少数几种与发育过程密切相关的通路之一，包括 Notch-Delta、Hedgehog、转化生长因子β（TGF-β）/骨形态发生蛋白（BMP）以及 Hippo 通路。这些信号通路在进化上高度保守且作用广泛。那么，与其他通路相比，Wnt 系统有何独特之处？Wnt 信号对细胞有哪些影响？为何该通路在生长组织中如此普遍活跃？本质上，Wnt 是促进生长的刺激因子，能够驱动细胞增殖（Niehrs 和 Acebron，2012 年）。在此过程中，Wnt 信号会影响细胞周期的多个环节。与其他生长因子不同，Wnt 信号通路的独特之处在于，它不仅能诱导细胞增殖，还能塑造生长组织的形态，起到定向生长因子的作用（Goldstein 等，2006 年；Huang 和 Niehrs，2014 年；Schneider 等，2015 年；Kitajima 等，2013 年；Loh 等，2016 年）。Wnt 信号能够指导新生细胞的定位，从而形成有序的机体结构，而非无序的组织（Huang 和 Niehrs，2014 年；Wu 等，2013 年；Habib 等，2013 年）。Wnt 信号这种形态发生效应是通过激活多级信号转导实现的，不仅改变基因表达，还会影响细胞骨架和纺锤体的功能（Sawa，2012 年）。 此外，Whts 通过利用不同类别的受体，产生了一系列对组合 Wnt 信号传导至关重要的多样性信号
correctly shaping tissues during development (van Amerongen and Nusse, 2009), or maintaining tissue architecture in adult life. In this overview of the field, we will mostly discuss the Wnt/ß-catenin (a.k.a. “canonical”) pathway, its nuclear effects, and implications for diseases, recognizing that to cover all aspects of Wnt signaling is beyond our scope.
在发育过程中正确塑造组织（van Amerongen 与 Nusse，2009 年），或维持成年期的组织结构。本文概述该领域时，我们将重点探讨 Wnt/ß-catenin（亦称“经典”）信号通路、其细胞核内效应及与疾病的关联，但需说明全面涵盖 Wnt 信号传导的所有内容非本文讨论范围。

There are multiple Wnt genes in any animal genome-19 in mammals for example (http://web.stanford.edu/group/nusselab/ cgi-bin/wnt/) - raising the question of specificity: do individual Whts have unique or overlapping functions? An argument for unique roles for each Wnt comes from loss-of-function genetic data: most Wnt genes, when eliminated from the genome, have distinct phenotypes. For example, mice mutant for Wnt1 have a midbrain defect (McMahon et al., 1992) while Wnt4 mutants are compromised in the development of the kidney (Stark et al., 1994). There are numerous other unique or partially overlapping phenotypes associated with loss of Wnt genes (http:// web.stanford.edu/group/nusselab/cgi-bin/wnt/) and, not surprisingly, the morphological phenotypes correspond to where the Wnts are expressed.
在各类动物基因组中均存在多个 Wnt 基因（如哺乳动物含 19 种，详见 http://web.stanford.edu/group/nusselab/cgi-bin/wnt/），由此引出一个关键问题：不同 Wnt 基因是否具有专属功能或功能重叠？来自基因敲除实验的证据支持其功能特异性——当特定 Wnt 基因被敲除后，往往会产生独特表型。例如，Wnt1 基因突变会导致小鼠中脑发育异常（McMahon 等人，1992），而 Wnt4 基因缺陷则影响肾脏形成（Stark 等人，1994）。现有数据库（http://web.stanford.edu/group/nusselab/cgi-bin/wnt/）还记载了大量其他具有独特性或部分重叠性的 Wnt 基因缺失表型，这些形态学异常与相应 Wnt 基因的表达谱高度吻合。

In addition to these genetic arguments, a case for inherent and important differences between individual Wnt signals comes from the high vertical evolutionary conservation of Wnt proteins. Orthologs within the Wnt family can be traced throughout all animal phyla: Wnt1 in mammals is the true ortholog of Wnt1 in Hydra and Wingless in Drosophila (Kusserow et al., 2005). Strikingly, Hydra and other Cnidaria have a set of Wnt genes that correspond one-to-one to vertebrate counterparts (Kusserow et al., 2005). Such a high degree of conservation and evolutionary constraint would argue that intrinsic properties of different Wnts are important for their functions.
除上述遗传学证据外，Wnt 蛋白在进化过程中表现出的高度保守性，也提示不同 Wnt 信号分子之间存在固有且重要的功能差异。研究表明，Wnt 家族直系同源基因广泛存在于所有动物门类中：例如哺乳动物的 Wnt1 基因与水螅的 Wnt1、果蝇的 Wingless 基因具有明确的同源关系（Kusserow 等，2005）。特别值得注意的是，水螅等刺胞动物体内存在一组与脊椎动物 Wnt 基因一一对应的同源基因（Kusserow 等，2005）。这种高度的进化保守性表明，不同 Wnt 分子所具有的内在特性对其生物学功能至关重要。

On the other hand, when it comes to biochemical signaling mechanisms or effects on target cells, different Whts behave in a very similar way. With respect to binding of Wnts to the receptors, the Frizzleds (FZDs), there is extensive cross-reactivity (Yu et al., 2012; Dijksterhuis et al., 2015). In addition, most Wnt
然而，在生化信号传导机制或对靶细胞的作用方面，不同 Wnt 蛋白的表现极为相似。就 Wnt 蛋白与 Frizzled（FZDs）受体的结合而言，存在广泛的交叉反应现象（Yu 等，2012；Dijksterhuis 等，2015）。此外，多数 Wnt

Figure 1. Model of Wht Secretion
图 1. Wht 蛋白分泌模型
In the endoplasmic reticulum, Wnts are modified by Porcupine (Porc) to become lipid-bound. Transport of the lipid-modified Wnt is regulated by Wntless/Evi (WIs), possibly involving endosomes. Whts are secreted on exocytic vesicles. Outside of cells, the Notum enzyme can act as a deacylase, removing the lipid and inactivating Wnt. After reception on the Wnt target cells by FZD and other receptors, cell-bound-Wnts may spread over tissues by cell division.
在内质网中，Wnt 蛋白经 Porcupine（Porc）修饰后与脂质结合。脂质修饰的 Wnt 蛋白的转运过程由 Wntless/Evi（WIs）调控，这一过程可能与内体相关。Wnt 蛋白通过外泌体囊泡分泌至胞外。在细胞外环境中，Notum 酶能发挥去酰基化作用，通过去除脂质修饰使 Wnt 蛋白失活。当 Wnt 蛋白被靶细胞表面的 FZD 等受体识别后，这些细胞膜结合的 Wnt 蛋白可通过细胞分裂在组织间传播。
proteins will lead to elevated levels of $\beta$$\beta$beta\beta-catenin in cells or increases in signaling reporter activity (Alok et al., 2017). These assays however, mostly done in cell culture, may not reveal the whole spectrum of signaling activity or receptor-binding finesses of different Wnts. As we will show below, there are various co-receptors for Whts that may modulate signaling outcome.
蛋白质会使细胞内的 $\beta$$\beta$beta\beta -catenin 水平升高，或增强信号报告活性（Alok 等，2017）。不过，这些主要在细胞培养中进行的实验，可能无法全面反映不同 Wnt 蛋白的信号活性特征或受体结合的精细调控。如下文所示，Whts 存在多种共受体，这些受体可能对信号输出结果起到调控作用。

Taking all these observations together, we suggest that, by and large, the differences between loss-of-function Wnt phenotypes can be attributed to discrete and unique expression patterns of the Wnt genes. Because of the fact that Wnt proteins signal very close to where they are produced, it seems that the overall phenotypes caused by loss of Wnt gene function are primarily due to local expression domains of each Wnt. In addition, intrinsic differences between Wnts, their binding to receptors and co-receptors are no doubt consequential for the various developmental processes as well.
综合上述观察结果，我们认为 Wnt 功能缺失导致的表型差异主要源于各 Wnt 基因独特的时空表达模式。由于 Wnt 蛋白仅在其合成部位附近发挥信号传导作用，因此 Wnt 基因缺失引发的整体表型差异本质上反映了各 Wnt 分子的局部表达特征。此外，不同 Wnt 配体间的固有特性差异、以及与受体/共受体结合的偏好性，也必然会对多种发育进程产生特异性影响。

Wnt proteins act as intercellular signals but there are several unresolved questions on the nature of the extracellular form of Wnts and the mechanisms of export. During synthesis, Wnt proteins, 40 kDa in size and rich in cysteines, are modified by attachment of a lipid, an acyl group termed palmitoleic acid (Willert et al., 2003; Rios-Esteves et al., 2014; Takada et al., 2006; Rios-Esteves and Resh, 2013). This modification is likely shared between all Wnts and is brought about by a special palmitoyl transferase: Porcupine (Rios-Esteves and Resh, 2013). The lipid functions primarily as a binding motif the Wnt receptor, FZD (see below) (Janda et al., 2012), but it also renders the Wnt protein hydrophobic and may tether it to cell membranes. The lipid may therefore contribute to restricting Wnt spreading and its range of action.
Wnt 蛋白作为细胞间信号分子发挥作用，但其细胞外形态及分泌机制仍存在多个悬而未决的问题。在合成阶段，分子量为 40 kDa 且富含半胱氨酸的 Wnt 蛋白会通过添加棕榈油酸（一种脂质酰基）发生修饰（Willert 等人，2003；Rios-Esteves 等人，2014；Takada 等人，2006；Rios-Esteves 和 Resh，2013）。这种修饰可能普遍存在于所有 Wnt 蛋白中，由特异性棕榈酰转移酶——Porcupine（豪猪蛋白）介导完成（Rios-Esteves 和 Resh，2013）。该脂质修饰不仅作为 Wnt 受体 Frizzled（FZD）的关键结合位点（详见下文）（Janda 等人，2012），还赋予 Wnt 蛋白疏水特性，使其能够锚定于细胞膜。这种特性可能正是限制 Wnt 信号扩散范围及其作用距离的重要机制。

During maturation of the Wnt protein, the transmembrane protein Wntless/Evi (WIs) (Bartscherer et al., 2006; Bänziger et al., 2006) binds to the lipidated forms (Yu et al., 2014; Herr and Bas-
Wnt 蛋白成熟过程中，跨膜蛋白 Wntless/Evi（简称 WIs，由 Bartscherer 等人在 2006 年及 Bänziger 等人在 2006 年发现）会与脂化修饰后的形式相结合（如 Yu 等人在 2014 年及 Herr 与 Bas-的研究所示）。
ler, 2012; Najdi et al., 2012) and is required for ferrying Wnts to the plasma membrane to become secreted (Figure 1). How extracellular Wnt signals are transferred to target cells remains mysterious, but available evidence suggests that the proteins are not present in a free form. More likely, Wnt proteins are incorporated into secretory vesicles or exosomes (Gross et al., 2012; Korkut et al., 2009; McGough and Vincent, 2016; Saha et al., 2016; Gross et al., 2012). These vesicles contain WIs as well as the mature Wnt signals (Korkut et al., 2009) (Figure 1),in such a form that the Wnt protein is present on the outside of the vesicle, available for binding to receptors. In another model, Wnt transfer involves direct contact between cells mediated by receptors FZD and the transmembrane E3 ligases Rnf43/Znrf3 (Farin et al., 2016) (Figure 1).
"ler（2012 年）和 Najdi 等人（2012 年）的研究表明，Wnt 蛋白需要被转运至细胞膜才能分泌（图 1）。目前，Wnt 信号如何传递给靶细胞仍不明确，但已有证据显示这些蛋白并非以游离形式存在。更可能的是，Wnt 蛋白会被包裹在分泌囊泡或外泌体中（Gross 等人，2012；Korkut 等人，2009；McGough 和 Vincent，2016；Saha 等人，2016）。这些囊泡不仅含有 WIs 蛋白，还携带成熟的 Wnt 信号分子（Korkut 等人，2009 年）（图 1）。在此过程中，Wnt 蛋白暴露于囊泡表面，便于与受体结合。另一种模型则认为，Wnt 信号的传递依赖于 FZD 受体与跨膜 E3 泛素连接酶 Rnf43/Znrf3 介导的细胞间直接接触（Farin 等人，2016 年）（图 1）。"

Although it is sometimes assumed that secreted Wnt signals are long-range morphogens, there is little evidence that this is the prevailing mode. In most tissues, Wnt signaling occurs between neighboring cells that contact each other. Even in the best studied example of long-range signaling by a Wnt-that is, by the Wnt ligand Wingless in Drosophila-recent evidence has made a case that the requirements for the gene can be largely provided by a membrane-tethered form of the protein which, in principle, cannot diffuse (Alexandre et al., 2014). While the conclusion of this result might be that Wingless does not act as a long-range morphogen, it could still be that Wingless bound to membranous vesicles or filopodia (Stanganello et al., 2015) would operate over longer distances. In support of the vesicle model, it has been shown that vesicles containing Wingless and its transporter protein Wntless/Evi are present at neuromuscular junctions in Drosophila and interact with FZD receptors (Korkut et al., 2009). Further alternatives to explain long-range activities by Wnts include sequential signaling between Wnt target cells and their neighbors, mediated by various Wnt family members. Indeed, Cnidaria embryos display staggered
虽然人们常假设分泌型 Wnt 信号可作为长程形态发生素，但鲜有证据表明这是其主要作用方式。在多数组织中，Wnt 信号传导仅发生于相互接触的相邻细胞间。即便在经典的长程 Wnt 信号案例——果蝇 Wingless 蛋白的研究中，最新证据表明该基因功能可通过膜锚定形式的蛋白实现（Alexandre 等，2014），而这种蛋白理论上无法自由扩散。虽然该研究暗示 Wingless 可能并非传统意义上的长程形态发生素，但结合膜泡或丝状伪足的 Wingless（Stanganello 等，2015）仍可能实现远距离调控。支持囊泡运输模型的证据显示，含有 Wingless 及其转运蛋白 Wntless/Evi 的囊泡存在于果蝇神经肌肉接头，并能与 FZD 受体互作（Korkut 等，2009）。其他解释 Wnt 长程活性的机制还包括：由不同 Wnt 家族成员介导的靶细胞与邻近细胞间的级联信号传递。值得注意的是，刺胞动物胚胎中确实存在这种梯度表达模式

Figure 2. Wnt Receptors  图 2. Wnt 信号通路受体
FZD proteins act as the primary receptors for Wnt signals. FZD molecules have 7-transmembrane (7TM) and an extracellular N-terminal cysteine-rich domain (CRD). Whts can bind the CRD of FZD. The co-receptors LRPs are long single-pass transmembrane proteins that are phosphorylated by several protein kinases including GSK3 and CK1. The Wnt agonists R-spondins interact on the cell surface with members of the LGR5 family to enhance Wnt signaling. ZNRF3 and RNF43 are transmembrane molecules that downregulate Wnt signaling. They have E3 ubiquitin ligase activity acting on the FZD molecules, leading to turn-over of these receptors. Binding of R-Spondin to ZNRF3 has been postulated to downregulate the activity of the ZNRF3 activity thereby enhancing Wnt signaling as the FZD receptors now become available.
FZD 蛋白是 Wnt 信号通路的首要受体，其分子结构包含 7 次跨膜区（7TM）及胞外 N 端富含半胱氨酸的结构域（CRD），后者可被 Wnt 配体结合。共受体 LRP 为单次跨膜的长链蛋白，能够被 GSK3、CK1 等多种激酶磷酸化。Wnt 信号增强因子 R-spondin 通过结合细胞表面的 LGR5 家族成员来强化信号传导。跨膜蛋白 ZNRF3 和 RNF43 则通过 E3 泛素连接酶作用促使 FZD 受体降解，从而抑制 Wnt 通路。当 R-Spondin 与 ZNRF3 结合时，可抑制后者的活性，减少 FZD 受体的降解，进而增强 Wnt 信号传导。
expression of various Wnt family members across the primary axis (Kusserow et al., 2005). In yet another context, stem cell niches of the intestinal crypts, Wnt protein bound to FZD receptor-expressing cells can become diluted as cells move and divide (Farin et al., 2016), a mode of Wnt transport that can also be directly visualized in intestinal organoid cultures (Figure 1). These results add to-but do not-resolve the continuing debate on the Wht signaling landscape and the existence of morphogens.
多种 Wnt 家族成员沿初级轴表达的现象已被报道（Kusserow 等，2005）。在肠隐窝干细胞微环境的研究中，与 FZD 受体结合后的 Wnt 蛋白会随细胞迁移和增殖发生浓度稀释（Farin 等，2016），这种 Wnt 信号传递模式在肠道类器官培养体系中可直接观测（图 1）。这些发现为 Wnt 信号梯度及形态发生素存在的学术争议提供了新证据，但尚未达成共识。

On the surface of cells, Wnt proteins bind to a receptor complex of two molecules, FZD (FZD) and LRP5/6 (Figure 2). FZD proteins have 7-transmembrane (7TM) and an extracellular N-terminal cysteine-rich domain (CRD) (Bhanot et al., 1996). The CRD is the primary interacting module for Wnt binding with affinities in the nM range (Hsieh et al., 1999). The structure of the CRD as bound to Wnt demonstrates that there are multiple interacting surfaces, including a hydrophobic pocket in the CRD that binds to the lipid on Wnt (Janda et al., 2012). In addition, the C terminus of Wnt makes contact with the CRD (Janda et al., 2012).
细胞表面，Wnt 蛋白会与由 FZD（FZD）和 LRP5/6 两种分子组成的受体复合物结合（见图 2）。FZD 蛋白含有 7 次跨膜结构域（7TM）及一个位于胞外的 N 端半胱氨酸富集结构域（CRD）（Bhanot 等，1996）。CRD 作为 Wnt 结合的核心区域，其亲和力可达纳摩尔级（Hsieh 等，1999）。CRD 与 Wnt 的复合物结构显示，两者存在多个相互作用界面，其中包括 CRD 中一个能结合 Wnt 脂质修饰的疏水口袋（Janda 等，2012）。此外，Wnt 蛋白的 C 端也会与 CRD 发生相互作用（Janda 等，2012）。

During signaling, FZDs cooperate with the single-pass transmembrane molecule LRP5/6, in such a way that binding of the Wnt protein leads to dimerization of the two receptors (Figure 2)
在信号传导过程中，FZD 受体通过与单次跨膜蛋白 LRP5/6 协同作用，当 Wnt 蛋白结合时，会引发这两种受体的二聚化反应（如图 2 所示）
(Janda et al., 2017). This mechanism would lead to a conformational change of the receptors. As a consequence, the cytoplasmic tail of LRP, after phosphorylation by several protein kinases, recruits the scaffold protein Axin. One of these phosphorylations on LRP is mediated by GSK3 on a serine in a PPPSP motif. The same motif is found in a number of Wnt signaling components including $\beta$$\beta$beta\beta-catenin, Axin, and APC (Stamos et al., 2014).
(Janda 等，2017)。该机制会引起受体构象变化，导致 LRP 的胞质尾部在被多种蛋白激酶磷酸化后募集支架蛋白 Axin。其中，GSK3 介导了 LRP 上 PPPSP 基序中一个丝氨酸的磷酸化。该基序同样存在于多个 Wnt 信号通路组分中，包括β-连环蛋白( $\beta$$\beta$beta\beta )、Axin 和 APC 等(Stamos 等，2014)。

While LRP has a relatively well-understood function in signaling, there is still little known about the role of FZD in Wnt reception. The cytoplasmic part of FZD can bind to Dishevelled (DVL) (Tauriello et al., 2012) (Figure 4) that would then provide a platform for the interaction between the LRP tail and Axin, through the DIX domain on DVL and Axin (Schwarz-Romond et al., 2007; Fiedler et al., 2011). Multimers of receptor-bound DVL and Axin molecules might support the formation of the LRP-FZD dimer. In line with this model, higher-order complexes containing Wnts, receptors, and DVL as well as small particles of multimerized DVL molecules have been detected in cells (Schwarz-Romond et al., 2005; Gammons et al., 2016; Jiang et al., 2015).
尽管 LRP 在信号传导中的功能已较为明确，但 FZD 在 Wnt 信号接收中的作用仍鲜为人知。FZD 的胞质区能够与 Dishevelled（DVL）结合（Tauriello 等，2012）（图 4），进而通过 DVL 和 Axin 蛋白的 DIX 结构域，为 LRP 尾部与 Axin 的相互作用提供分子平台（Schwarz-Romond 等，2007；Fiedler 等，2011）。受体结合的 DVL 与 Axin 形成的多聚体可能促进 LRP-FZD 二聚体的组装。支持这一模型的是，研究人员已在细胞内观测到含有 Wnt 配体、受体、DVL 的高阶复合物，以及 DVL 多聚化形成的小颗粒结构（Schwarz-Romond 等，2005；Gammons 等，2016；Jiang 等，2015）。
Wnts are not the only ligands of the FZD receptors. The cysteine-knot protein Norrin, encoded by the NDP gene, can also bind and activate Wnt receptors (Figure 3). In humans,
Wnt 蛋白并非 FZD 受体的唯一配体。由 NDP 基因编码的含胱氨酸结结构的 Norrin 蛋白同样能够结合并激活 Wnt 受体（见图 3）。在人类中，

Figure 3. Alternative Wnt Receptors
图 3. 替代型 Wnt 受体
(A) In regulating the blood-brain-barrier and possibly other areas of vasculature, Wnt7 can interact with not only FZD4 and LRP, but also with the multiple pass transmembrane protein Gpr124. During vascular development. Norrin can also act as a ligand for the FZD4/LRP5 complex. The tetraspanin family member, Tspan12, can be a Norrin-specific co-receptor.
"(A) 在调控血脑屏障及其他血管区域时，Wnt7 不仅能与 FZD4 和 LRP 相互作用，还能与多次跨膜蛋白 Gpr124 发生作用。在血管发育过程中，Norrin 也可作为 FZD4/LRP5 复合体的配体。而四跨膜蛋白家族成员 Tspan12，则能作为 Norrin 的特异性共受体发挥作用。"
(B) The RYK proteins are transmembrane tyrosine kinases. They have a Wnt binding domain similar to the WIF proteins. The ROR transmembrane tyrosine kinases can also bind to Wnts using a CRD motif similar to that of the FZDs.
(B) RYK 蛋白属于跨膜酪氨酸激酶家族，其 Wnt 结合域结构与 WIF 蛋白相似。此外，ROR 跨膜酪氨酸激酶也能通过类似 FZD 受体的 CRD 结构域与 Wnt 蛋白结合。

NDP mutations cause Norrie disease, an X-linked disorder characterized by hypovascularization of the retina and a severe loss of visual function. Norrin binds with high affinity and specificity to FZD-4 (Ke et al., 2013; Chang et al., 2015), while coexpression of Norrin, FZD-4, and LRP5 potently activates Wnt/ $\beta$$\beta$beta\beta-catenin signaling (Xu et al., 2004). Biochemical evidence and analyses of mice carrying mutations in the tetraspanin family member, Tspan12, provide evidence that Tspan12 is a Norrin-specific co-receptor (Figure 3) (Junge et al., 2009) that may act by forming a ternary complex with FZD4 (Ke et al., 2013).
NDP 基因突变会引发 Norrie 病，这是一种 X 染色体连锁遗传病，临床表现为视网膜血管发育不良及视力功能严重受损。研究表明，Norrin 蛋白能以高亲和力和特异性与 FZD-4 受体结合（Ke 等，2013；Chang 等，2015），当 Norrin、FZD-4 与 LRP5 共同表达时，可显著激活 Wnt/ $\beta$$\beta$beta\beta -catenin 信号通路（Xu 等，2004）。通过生化实验及对 Tspan12（四跨膜蛋白家族成员）突变小鼠的分析证实，Tspan12 是 Norrin 的特异性辅助受体（图 3）（Junge 等，2009），其作用机制可能是与 FZD4 形成三元复合物（Ke 等，2013）。

Interestingly, FZD can also act as a receptor for the Clostridium difficile toxin B (TcdB) (Tao et al., 2016), a toxin known to be a critical virulence factor in causing diseases after infection by C. difficile infection. TcdB can bind to the CRD of FZD, with different affinities for several FZD family members. As TcdB can actually compete with Wnt for binding to FZDs and blocks Wnt signaling, the pathology underlying C. difficile infection could be caused by loss of Wnt signaling in the intestine, a supposition that offers hope for therapeutic intervention in $C$$C$CC. difficile infections (Tao et al., 2016).
值得注意的是，FZD 蛋白还能作为艰难梭菌毒素 B（TcdB）的受体（Tao 等，2016）。TcdB 是导致艰难梭菌感染后发病的关键毒力因子，它能与 FZD 蛋白的 CRD 结构域结合，且对不同 FZD 家族成员的结合亲和力存在差异。由于 TcdB 可与 Wnt 竞争性结合 FZD 并阻断 Wnt 信号通路，因此艰难梭菌感染的致病机制可能与肠道 Wnt 信号通路功能丧失有关。这一发现为 $C$$C$CC 艰难梭菌感染的治疗提供了新的干预思路（Tao 等，2016）。

In addition to the core receptors FZD and LRP5/6, there are several other transmembrane molecules implicated in Wnt signaling. These include the ROR and RYK tyrosine kinase receptors, able to bind to Wnt ligands using a CRD or WIF domain respectively (Figure 3). Once activated, these receptors feed into other signaling pathways in cells. Each of them has also been shown to interact with DVL, leading to the phosphorylation of this common Wnt pathway component. The consequences of these DVL modifications are otherwise unknown (Ho et al., 2012; Huang et al., 2013).
除核心受体 FZD 和 LRP5/6 外，另有多种跨膜分子参与 Wnt 信号通路调控，其中包括 ROR 和 RYK 酪氨酸激酶受体。二者分别通过 CRD 结构域或 WIF 结构域与 Wnt 配体结合（图 3）。受体激活后，可进一步调控细胞内其他信号通路。研究还发现，这些受体均能与 Wnt 通路关键蛋白 DVL 相互作用并诱导其磷酸化，但 DVL 修饰后的具体功能仍不明确（Ho 等，2012；Huang 等，2013）。

Yet another receptor, GPR 124, is required for correct Wnt signaling in establishing the blood brain barrier (Zhou and Nathans, 2014; Posokhova et al., 2015). Here, Wnt7 is the locally acting ligand, working through FZD and LRP, but whether Wnt7A binds directly to the multiple pass transmembrane protein GPR124 is not clear (Figure 3) (Zhou and Nathans, 2014).
另一种受体 GPR124 是形成血脑屏障过程中 Wnt 信号通路正常运作所必需的（Zhou 和 Nathans，2014；Posokhova 等，2015）。其中，Wnt7 作为局部作用配体，通过 FZD 和 LRP 受体发挥作用，但 Wnt7A 是否能直接与多次跨膜蛋白 GPR124 结合目前尚未明确（图 3）（Zhou 和 Nathans，2014）。

Whether all of these Wnt receptors, including ROR, RYK and GPR124 cooperate on cells, forming higher order structures, or operate independently is a major question that would require the development of new assays. Going back to the structure of the Wnt-FZD complex, it is striking that there is extensive surface left between the two separate binding domains on Wnt for FZD, suggesting that other molecules, including other receptors could participate in the complex leading to productive signaling.
这些 Wnt 受体（如 ROR、RYK 和 GPR124）究竟是在细胞上协同作用形成高阶结构，还是各自独立发挥作用，仍是一个关键科学问题，有待开发新型检测手段来解答。从 Wnt-FZD 复合物的结构来看，值得注意的是，Wnt 蛋白上两个 FZD 结合域之间仍存在大量未占用的表面区域，这暗示其他受体分子可能参与复合物组装，共同激活下游信号通路。

As is commonly seen in signaling pathways, Wnt activity is regulated by extracellular proteins that antagonize the ligand. A recent example is Notum, originally discovered in Drosophila as an enzyme, a carboxylesterase that can remove the palmitoleate modification on Wnt (Kakugawa et al., 2015; Zhang et al., 2015) (Figure 1). As mentioned before, this palmitoleate is essential for signaling and participates in the binding of Wnt to FZD. The structure of Notum shows a large hydrophobic pocket in the protein that accommodates a palmitoleate moiety. Hydrolysis of the palmitoleate by Notum could leave an intact Wnt protein outside of cells, where it could act as a dominant interfering molecule, although this is presently unknown.
在信号通路中，Wnt 的活性通常受到细胞外拮抗蛋白的调控。Notum 便是最新发现的一例，它最初在果蝇中被鉴定为一种羧酸酯酶，能够特异性去除 Wnt 蛋白的棕榈油酸修饰（Kakugawa 等，2015；Zhang 等，2015）（图 1）。该棕榈油酸修饰对 Wnt 信号传导至关重要，介导 Wnt 与 FZD 受体的结合。Notum 的蛋白结构显示其具有一个大型疏水口袋，可容纳棕榈油酸基团。Notum 通过水解作用去除棕榈油酸后，虽可能使完整的 Wnt 蛋白滞留于胞外并发挥显性负效应，但这一机制尚待证实。

Other Wnt antagonists include proteins of the Dickkopf (DKK) and the Sclerostin/SOST families (Cruciat and Niehrs, 2013). These molecules antagonize Wnt signaling by binding LRP5/6, possibly disrupting Wnt-induced FZD-LRP6 dimerization (Cruciat and Niehrs, 2013). Wnt-interfering molecules also include the secreted FZD-related proteins (sFRPs) and Wnt inhibitory protein (WIF) proteins, both able to bind to Wnts directly. Taken altogether, a picture emerges of a complex extracellular landscape of Wnt-modifying and Wnt-binding factors, fine-tuning the strength of signaling (Niehrs, 2012).
其他 Wnt 信号通路的拮抗剂包括 Dickkopf（DKK）家族蛋白和 Sclerostin/SOST 家族蛋白（Cruciat 与 Niehrs，2013）。这类分子通过结合 LRP5/6 受体来抑制 Wnt 信号传导，其机制可能是干扰 Wnt 诱导的 FZD-LRP6 二聚体形成（Cruciat 与 Niehrs，2013）。此外，分泌型卷曲相关蛋白（sFRPs）和 Wnt 抑制因子（WIF）也能直接与 Wnt 蛋白结合。这些研究共同揭示了一个由多种 Wnt 调控因子构成的复杂胞外调控网络，可精确调节信号传导强度（Niehrs，2012）。
Two highly homologous Wnt target genes, Rnf43 and Znrf3, were recently identified as potent negative-feedback regulators of Wnt signal strength. The two proteins were originally identified to be specific to the Wht-dependent Lgr5 stem cells of crypts
近期研究发现，Rnf43 和 Znrf3 这两个高度同源的 Wnt 靶基因，是调控 Wnt 信号强度的强效负反馈因子。这两种蛋白质最初被发现在依赖 Wnt 信号的隐窝 Lgr5 干细胞中特异性表达
(Koo et al., 2012) and to be enriched in colon cancer cells that carry activating Wnt pathway mutations (Hao et al., 2012). Like the founding member of this family, Grail, the two proteins are single-pass transmembrane E3 ligases carrying intracellular RING domains. Rnf43 and Znrf3 specifically mediate multi-ubiquitination of lysines in the cytoplasmic loops of the 7TM domain of FZDs (Figure 2) (Hao et al., 2012; Koo et al., 2012). This induces rapid endocytosis and lysosomal destruction of the Wnt receptors. The orthologous C. elegans PLR-1 E3 ligase A similarly abrogates FZD surface expression (Moffat et al., 2014). The structural basis for how the E3 ligases identify FZDs as their specific substrates is currently not exactly known, although it has been proposed that DVL proteins act as intermediaries in the recognition process (Jiang et al., 2015).
（Koo 等，2012）研究发现，这类蛋白在携带 Wnt 通路激活突变的结肠癌细胞中显著富集（Hao 等，2012）。与家族首个成员 Grail 类似，Rnf43 和 Znrf3 都是具有胞内 RING 结构域的单次跨膜 E3 泛素连接酶。它们能特异性介导 FZD 受体七次跨膜结构域胞质环中赖氨酸残基的多泛素化修饰（图 2）（Hao 等，2012；Koo 等，2012），从而促使 Wnt 受体发生快速内吞并被溶酶体降解。在线虫中，其同源蛋白 PLR-1 E3 连接酶也表现出类似的 FZD 膜表达抑制功能（Moffat 等，2014）。目前虽提出 DVL 蛋白可能作为识别过程中的桥梁分子（Jiang 等，2015），但 E3 连接酶特异性识别 FZD 受体的结构基础尚未完全阐明。

Loss of these two E3 ligases is predicted to result in hyperresponsiveness to endogenous Wnt signals. Indeed, co-deletion of these two Wnt modulators in murine intestinal epithelium induces an adenomatous expansion of the crypts (Koo et al., 2012), which disappears upon treatment with small molecule inhibitors of the Porcupine enzyme (required for the critical lipid modification of Wnt) (Koo et al., 2015). Mutations in Rnf43 and Znrf3 have been observed in a variety of human cancers, rendering the malignant cells dependent on much lower levels of Wnt than their healthy counterparts and sensitive to inhibition at the Wnt receptor ligand level (see below).
预测这两种 E3 泛素连接酶的缺失会导致细胞对内源性 Wnt 信号过度敏感。实验证实，在小鼠肠道上皮细胞中同时敲除这两种 Wnt 调控因子后，会引发隐窝腺瘤样增生（Koo 等，2012）。而使用 Porcupine 酶（Wnt 蛋白关键脂质修饰必需酶）的小分子抑制剂处理后，这种增生现象可被消除（Koo 等，2015）。研究发现，Rnf43 和 Znrf3 基因突变存在于多种人类癌症中，这些突变使癌细胞相比正常细胞能在更低 Wnt 水平下存活，并对 Wnt 受体-配体通路的抑制治疗表现出敏感性（详见下文分析）。

The vertebrate genome harbors four secreted R -spondin proteins, each carrying two N-terminal furin domains and a thrombospondin domain. Kazanskaya et al. (2004) first identified the R-spondins as Wnt signal enhancers in Xenopus embryos. R-spondin-1 was subsequently shown to potently promote Wnt-dependent intestinal crypt proliferation in vivo (Kim et al., 2005) and in vitro (Sato et al., 2009). Three members of a small family of 7-TM receptors, Lgr4, Lgr5, and Lgr6 family, bind R-spondins with high affinity and are essential for signal enhancement of low dose Wnt (Carmon et al., 2011; de Lau et al., 2011; Glinka et al., 2011). The Lgr proteins bind R-spondins through their N -terminal ectodomain and do not appear to utilize G-proteins (Carmon et al., 2011; de Lau et al., 2011).
脊椎动物基因组中含有四种分泌型 R-spondin 蛋白，每种蛋白均包含两个 N 端弗林结构域和一个血小板反应蛋白结构域。Kazanskaya 等研究者于 2004 年首次在非洲爪蟾胚胎中发现这类蛋白具有增强 Wnt 信号的功能。随后的研究证实，R-spondin-1 无论在活体（Kim 等，2005）还是体外培养（Sato 等，2009）条件下，都能显著促进依赖 Wnt 信号的肠道隐窝细胞增殖。Lgr 家族中的三个七次跨膜受体成员——Lgr4、Lgr5 和 Lgr6，能以高亲和力与 R-spondin 蛋白结合，这对增强低浓度 Wnt 信号至关重要（Carmon 等，2011；de Lau 等，2011；Glinka 等，2011）。值得注意的是，Lgr 蛋白通过其 N 端胞外结构域与 R-spondin 结合，且该过程不依赖 G 蛋白信号通路（Carmon 等，2011；de Lau 等，2011）。

The prototype member of the Lgr-subfamily, Lgr5, was already known to mark adult stem cells in a number of actively selfrenewing organs, notably of the intestine (Barker et al., 2007). A strong genetic interaction was described to exist between Lgr4 and Lgr5 in the maintenance of Wnt signal strength in crypts of double mutant mice (de Lau et al., 2011). In recent work, it was shown that Wnts by themselves are not sufficient for selfrenewal of Lgr5 ${}^{+}$${}^{+}$^(+){ }^{+}stem cells but instead confer competency by maintaining Rspo receptor expression and resulting stem cell expansion (Yan et al., 2017).
"作为 Lgr 亚家族的原型成员，Lgr5 已被证实可在多个具有持续自我更新能力的器官（特别是肠道）中标记成体干细胞（Barker 等，2007）。研究发现，在双基因突变小鼠的肠隐窝中，Lgr4 与 Lgr5 之间存在显著的遗传互作关系，共同调控 Wnt 信号通路活性（de Lau 等，2011）。最新研究表明，Wnt 信号分子本身并不足以维持 Lgr5 阳性干细胞的自我更新，而是通过持续激活 Rspo 受体表达来维持干细胞的增殖潜能（Yan 等，2017）。"

Lgr6 similarly marks stem cells in the skin (Füllgrabe et al., 2015; Snippert et al., 2010). Thus, the notion that the Lgr proteins act as receptors for R -spondins reinforced the intimate connection between Wnt signaling and adult stem cell biology.
Lgr6 同样在皮肤中标记干细胞（Füllgrabe 等，2015；Snippert 等，2010）。由此可见，Lgr 蛋白作为 R-spondins 受体的作用，进一步印证了 Wnt 信号通路与成体干细胞生物学之间的密切关联。

But how do R-spondins and Lgrs amplify Wnt signals? Hao et al. (2012) performed a series of biochemical experiments that showed that R-spondins in an Lgr-dependent manner
然而 R-spondins 与 Lgrs 是如何增强 Wnt 信号的呢？Hao 等人(2012 年)通过一系列生化实验证实，R-spondins 以依赖 Lgr 的方式发挥作用
reversed the Rnf43/Znrf3-mediated membrane clearance of Wnt receptors. A weak yet specific interaction of R-spondin with Znrf3 was observed. A model, strengthened by X-ray crystallography (de Lau et al., 2014), was then formulated in which R-spondin’s high-affinity interaction with Lgr5 through its Furin-2 repeat, allows the other Furin repeat in R-spondin to interact with Rnf43/Znrf3. This in turn would result in membrane clearance of the E3 ligases and persistence of activated Wnt/ FZD/LRP receptor complexes on the plasma membrane, boosting Wnt signal strength and duration (Figure 2).
研究发现 R-spondin 能够抑制 Rnf43/Znrf3 对 Wnt 受体的膜清除作用，并观察到其与 Znrf3 存在特异性弱相互作用。基于 X 射线晶体学研究（de Lau 等，2014）的支持，研究者提出一个模型：R-spondin 通过其 Furin-2 重复结构域与 Lgr5 发生高亲和力结合，同时利用另一个 Furin 重复结构域与 Rnf43/Znrf3 相互作用。这种双重作用导致 E3 泛素连接酶被清除出膜，使得激活的 Wnt/FZD/LRP 受体复合物稳定存在于细胞膜上，从而显著增强并延长 Wnt 信号通路的活性（如图 2 所示）。
While Rnf43/Znrf3 homologs exist in invertebrates, the R-spondin/Lgr5/Rnf43 module is a recent evolutionary “addon” seen only in vertebrates and by-and-large dedicated to adult stem cells. The evolutionary emergence of sophisticated stem cell/transit amplifying cell compartments in vertebrates coinciding with the general increase in vertebrate body size may have been facilitated by this novel mechanism of Wnt signal amplification.
尽管无脊椎动物中存在 Rnf43/Znrf3 的同源基因，但 R-spondin/Lgr5/Rnf43 这一调控模块是脊椎动物特有的进化新特征，主要作用于成体干细胞。该机制通过增强 Wnt 信号通路，可能促进了脊椎动物在进化过程中形成精密的干细胞/增殖细胞层级结构，并与其体型增大现象密切相关。

The key switch in the canonical Wnt pathway is the cytoplasmic protein $\beta$$\beta$beta\beta-catenin (Figure 4). Its stability is controlled by the destruction complex (DC). In this complex, the tumor suppressor protein Axin acts as the scaffold, interacting with $\beta$$\beta$beta\beta-catenin, the tumor suppressor protein APC, and two constitutively active serine-threonine kinases (CK1 $\alpha /\delta$$\alpha /\delta$alpha//delta\alpha / \delta and GSK3 $\alpha /\beta$$\alpha /\beta$alpha//beta\alpha / \beta ). The large APC protein contains three Axin-binding motifs that are interspersed between a series of 15- and 20 -amino acid repeats that bind $\beta$$\beta$beta\beta-catenin. Although it is clear from studies on colorectal cancer that APC is essential for DC function, its specific molecular activity has only partially been resolved (Figure 4).
经典 Wnt 信号通路的核心调控元件是细胞质中的 $\beta$$\beta$beta\beta -β连环蛋白（图 4）。其稳定性受破坏复合物（DC）调控。该复合物中，肿瘤抑制蛋白 Axin 作为支架蛋白，分别与 $\beta$$\beta$beta\beta -β连环蛋白、肿瘤抑制蛋白 APC 以及两种组成型激活的丝氨酸-苏氨酸激酶（CK1 $\alpha /\delta$$\alpha /\delta$alpha//delta\alpha / \delta 和 GSK3 $\alpha /\beta$$\alpha /\beta$alpha//beta\alpha / \beta ）相互作用。APC 作为大分子蛋白含有三个 Axin 结合模体，这些模体分布于多个 15 和 20 氨基酸重复序列之间，这些重复序列可结合 $\beta$$\beta$beta\beta -β连环蛋白。虽然结直肠癌研究已证实 APC 对 DC 功能不可或缺，但其精确的分子机制至今尚未完全阐明（图 4）。

When Fz/LRP receptors are not engaged by ligands, CK1 and GSK3 sequentially phosphorylate Axin-bound $\beta$$\beta$beta\beta-catenin at a series of regularly spaced $N$$N$NN-terminal Ser/Thr moieties: $\beta$$\beta$beta\beta-catenin is first phosphorylated by CK1 at Ser45, followed by GSK3 phosphorylation at Thr41, Ser37, and Ser33 residues (Liu et al., 2002). The phosphorylated “degron”-motif acts as a docking site for the F-box-containing protein E3 ubiquitin ligase $\beta$$\beta$beta\beta-TrCP inducing ubiquitination and subsequent proteasomal degradation of $\beta$$\beta$beta\beta-catenin (Aberle et al., 1997; Kitagawa et al., 1999) (Figure 4). Receptor engagement relocalizes the DC to the cell membrane and interferes with its activity such that free $\beta$$\beta$beta\beta-catenin levels rapidly increase. At the same time, the phosphorylated LRP receptor may act to inhibit GSK-3 directly and thereby promote $\beta$$\beta$beta\beta-catenin stabilization (Stamos et al., 2014). Biochemical scrutiny of the endogenous DC has revealed that ubiquitination of phosphorylated $\beta$$\beta$beta\beta-catenin is blocked within the intact complex. As a consequence, the complex becomes saturated by the phosphorylated form of $\beta$$\beta$beta\beta-catenin, leading to accumulation of newly synthesized $\beta$$\beta$beta\beta-catenin, free to translocate to the nucleus and to activate target genes (Li et al., 2012; Azzolin et al., 2014). As an alternative mechanism, it has been proposed that Wnt receptor engagement models result in the dynamic regulation of $\beta$$\beta$beta\beta-catenin phosphorylation (Hernández et al., 2012) and phosphorylation-regulated Axin-complex disassembly (Kim et al., 2013). Several studies have identified a highly conserved
当 Fz/LRP 受体未与配体结合时，CK1 和 GSK3 会依次磷酸化 Axin 结合的 $\beta$$\beta$beta\beta -catenin 上规则排列的 $N$$N$NN 端丝氨酸/苏氨酸残基：首先，CK1 在 Ser45 位点磷酸化 $\beta$$\beta$beta\beta -catenin，随后 GSK3 进一步磷酸化 Thr41、Ser37 和 Ser33 位点（Liu 等，2002）。这些磷酸化形成的“degron”降解信号基序会招募含 F-box 的 E3 泛素连接酶 $\beta$$\beta$beta\beta -TrCP，介导 $\beta$$\beta$beta\beta -catenin 的泛素化修饰并最终被蛋白酶体降解（Aberle 等，1997；Kitagawa 等，1999）（图 4）。当受体被激活后，DC 复合物被募集至细胞膜，其活性受到抑制，导致游离的 $\beta$$\beta$beta\beta -catenin 水平快速上升。同时，磷酸化的 LRP 受体可直接抑制 GSK-3 活性，从而稳定 $\beta$$\beta$beta\beta -catenin（Stamos 等，2014）。对细胞内 DC 复合物的生化分析显示，磷酸化的 $\beta$$\beta$beta\beta -catenin 在完整复合物中无法被泛素化。这使得复合物被磷酸化的 $\beta$$\beta$beta\beta -catenin 饱和，新合成的 $\beta$$\beta$beta\beta -catenin 得以积累，并自由进入细胞核激活靶基因表达（Li 等，2012；Azzolin 等，2014）。 "作为替代机制，有研究提出 Wnt 受体结合模型可动态调控 $\beta$$\beta$beta\beta -β连环蛋白的磷酸化过程（Hernández 等，2012），并通过磷酸化作用调节 Axin 复合体的解聚（Kim 等，2013）。多项研究表明该机制具有高度保守性"

Figure 4. Wnt Signaling in Cells
图 4. 细胞内的 Wnt 信号通路
Left: In the absence of a Wnt signal, $\beta$$\beta$beta\beta-catenin is degraded by a complex of proteins including Axin, APC, the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase $\beta$$\beta$beta\beta-TrCP. The complex specifies a $\beta$$\beta$beta\beta-TrCP recognition site on $\beta$$\beta$beta\beta-catenin by phosphorylation of a conserved Ser/Thrrich sequence near the amino terminus. Phosphorylation requires scaffolding of GSK-3 and CK1 and $\beta$$\beta$beta\beta-catenin by Axin. After phosphorylation and ubiquitination, $\beta$$\beta$beta\beta-catenin is degraded by the proteasome. SCF, the Skp1/cullin/F-box complex. Dvl (Disheveled) is required for activating the pathway as well. In the nucleus, T cell factor (TCF) is in an inactive state as the consequence of binding to the repressor Groucho.
左侧：当缺乏 Wnt 信号时， $\beta$$\beta$beta\beta -catenin 会被一个由 Axin、APC、Ser/Thr 激酶 GSK-3 和 CK1、蛋白磷酸酶 2A（PP2A）以及 E3 泛素连接酶 $\beta$$\beta$beta\beta -TrCP 组成的蛋白复合体降解。该复合体通过磷酸化 $\beta$$\beta$beta\beta -catenin 氨基末端附近一段保守的 Ser/Thr 富集序列，形成 $\beta$$\beta$beta\beta -TrCP 识别位点。这一磷酸化过程依赖于 Axin 对 GSK-3、CK1 和 $\beta$$\beta$beta\beta -catenin 的支架作用。完成磷酸化和泛素化修饰后， $\beta$$\beta$beta\beta -catenin 被蛋白酶体降解。其中，SCF 指 Skp1/cullin/F-box 蛋白复合体，而 Dvl（Disheveled）蛋白也是通路激活所必需的因子。在细胞核内，T 细胞因子（TCF）因与抑制因子 Groucho 结合而处于失活状态。
Center: Binding of Wnt to its receptors induces the association of Axin with phosphorylated lipoprotein receptor-related protein (LRP). The destruction complex falls apart, and $\beta$$\beta$beta\beta-catenin is stabilized, subsequently binding TCF in the nucleus to upregulate target genes.
"核心过程：Wnt 蛋白与受体结合后，促使 Axin 与磷酸化的低密度脂蛋白受体相关蛋白（LRP）结合。这导致β-catenin 降解复合体解体，使β-catenin 得以稳定存在并进入细胞核，与 TCF 转录因子结合，进而激活下游靶基因的表达。"
Right: Mutations in APC disrupt the degradation complex and thereby lead to activation of the pathway.
右侧：APC 基因突变会破坏降解复合体，进而导致该信号通路被激活。
regulatory domain in APC, the $\beta$$\beta$beta\beta-catenin inhibitory domain (CID), located between the second and the third 20-amino acid repeats (Kohler et al., 2009; Roberts et al., 2011). The CID is believed to be essential for downregulating $\beta$$\beta$beta\beta-catenin levels and Wnt transcriptional activity. In agreement, the CID is located right at the mutation cluster region, the site of common truncation of APC in cancer. The CID has been proposed to promote $\beta$$\beta$beta\beta-catenin ubiquitination by stabilizing the association with APC as well as to repress $\beta$$\beta$beta\beta-catenin/TCF transcription in the nucleus (Choi et al., 2013). A more recent study proposed another model: GSK3-mediated phosphorylation around the CID region induces a conformational change in the APC protein that allows accessibility of the E3-ligase to phospho- $\beta$$\beta$beta\beta-catenin (Figure 4) (Pronobis et al., 2015).
APC 蛋白的调控结构域——β-连环蛋白抑制域（CID）位于第二个与第三个 20-氨基酸重复序列之间（Kohler 等，2009；Roberts 等，2011）。该结构域对降低β-连环蛋白含量及抑制 Wnt 信号通路的转录活性具有关键作用。值得注意的是，CID 恰好位于癌症中 APC 蛋白高频突变的"突变簇区域"。研究表明，CID 既能通过稳定 APC 蛋白的结合来促进β-连环蛋白的泛素化降解，也能在细胞核内抑制β-连环蛋白/TCF 转录活性（Choi 等，2013）。最新研究还发现，GSK3 激酶对 CID 区域的磷酸化修饰会引发 APC 蛋白构象改变，从而使 E3 泛素连接酶能够识别磷酸化的β-连环蛋白（图 4）（Pronobis 等，2015）。

Complicating its analysis, $\beta$$\beta$beta\beta-catenin plays a second, major role in epithelia. It is an essential binding partner for the cytoplasmic tail of various cadherins, such as E-cadherin in adhesion junctions (Peifer et al., 1992). While the half-life of the signaling pool of $\beta$$\beta$beta\beta-catenin is in the order of minutes, the adherens junc-tion-pool is highly stable. The adhesive and signaling properties of $\beta$$\beta$beta\beta-catenin are most likely independent. Indeed, in C. elegans
"进一步分析发现， $\beta$$\beta$beta\beta -连环蛋白在上皮细胞中还发挥着另一个重要作用。作为多种钙粘蛋白（如粘附连接中的 E-钙粘蛋白）胞质尾端的关键结合配体（Peifer 等，1992），其信号通路的 $\beta$$\beta$beta\beta -连环蛋白半衰期仅数分钟，而粘着连接处的蛋白却异常稳定。 $\beta$$\beta$beta\beta -连环蛋白的粘附功能与信号传导特性很可能是相互独立的。这一点在秀丽隐杆线虫中表现得尤为明显"
the two functions of $\beta$$\beta$beta\beta-catenin are performed by distinct homologs (Korswagen et al., 2000).
" $\beta$$\beta$beta\beta -catenin 的两种功能分别由不同的同源蛋白承担（Korswagen 等, 2000）。"

Canonical Wnt signaling leads to a defined cellular response through the activation of $\beta$$\beta$beta\beta-catenin/TCF target genes (Figure 4). Upon Wnt pathway activation, $\beta$$\beta$beta\beta-catenin accumulates in the cytoplasm and nucleus, where it engages DNA-bound TCF transcription factors (Behrens et al., 1996; Molenaar et al., 1996). The cognate TCF binding motif is $5^{\prime }$$5^{\prime }$5^(')5^{\prime}-AGATCAAAGG- $3^{\prime }$$3^{\prime }$3^(')3^{\prime} (van de Wetering et al., 1997). Widely used Wnt/TCF reporters such as pTOPflash (Korinek et al., 1997) contain multimers of this motif. In the Wnt “off” state, Tcfs interact with Groucho proteins to mediate transcriptional repression (Cavallo et al., 1998; Roose et al., 1998). In the Wnt “on” state, engagement of $\beta$$\beta$beta\beta-catenin transiently converts TCF into a transcriptional activator (Figure 4). While most Wnt target genes are cell-type- and developmental stage-specific, the Axin2 gene represents a generic transcriptional target gene, often used as indicator of canonical Wnt pathway activity (Lustig et al., 2002). Active Wnt signaling may involve an increase in overall $\beta$$\beta$beta\beta-catenin levels without any
经典 Wnt 信号通路通过激活 $\beta$$\beta$beta\beta -β-catenin/TCF 靶基因，引发明确的细胞应答（如图 4 所示）。当 Wnt 通路激活时， $\beta$$\beta$beta\beta -β-catenin 会在细胞质和细胞核内累积，并与 DNA 结合的 TCF 转录因子相结合（Behrens 等人，1996；Molenaar 等人，1996）。其对应的 TCF 结合基序为 $5^{\prime }$$5^{\prime }$5^(')5^{\prime} -AGATCAAAGG- $3^{\prime }$$3^{\prime }$3^(')3^{\prime} （van de Wetering 等人，1997）。常用的 Wnt/TCF 报告系统（如 pTOPflash，Korinek 等人，1997）即包含该基序的多聚体。在 Wnt 通路"关闭"状态下，TCF 蛋白会与 Groucho 蛋白相互作用，介导转录抑制（Cavallo 等人，1998；Roose 等人，1998）。而当 Wnt 通路"开启"时， $\beta$$\beta$beta\beta -β-catenin 的参与可短暂地将 TCF 转化为转录激活因子（见图 4）。虽然大多数 Wnt 靶基因具有细胞类型和发育阶段特异性，但 Axin2 基因作为通用转录靶标，常被用作经典 Wnt 通路活性的标志物（Lustig 等人，2002）。活跃的 Wnt 信号传导可能导致 $\beta$$\beta$beta\beta -β-catenin 总体水平的升高，而无需其他条件。
detectable nuclear accumulation. It has been suggested that fold-change rather than absolute $\beta$$\beta$beta\beta-catenin levels are critical, implying that, indeed, low levels of nuclear $\beta$$\beta$beta\beta-catenin suffice for target gene activation (Goentoro and Kirschner, 2009). Multiple non-TCF transcription factors have been implied as alternative transcriptional effectors. These studies typically await independent confirmation. Contrasting with these studies, recent genome-wide approaches in mammalian cells (Schuijers et al., 2014) and Drosophila (Franz et al., 2017) imply that all direct activation of $\beta$$\beta$beta\beta-catenin target genes involves TCFs as final effectors. $\beta$$\beta$beta\beta-catenin, once recruited to promoter and enhancer elements, activates gene transcription through its C-terminal transcriptional activation domain (van de Wetering et al., 1997). It binds chromatin modifiers such as CBP and $\mathrm{Brg}-1$$\mathrm{Brg}-1$Brg-1\mathrm{Brg}-1 (reviewed in (Städeli et al., 2006) and Parafibromin/Hyrax, homologs of yeast Cdc73 (Mosimann et al., 2006).
"研究表明，β-连环蛋白的核积累是可检测的，且关键在于其水平的变化倍数而非绝对值，这意味着即使核内β-连环蛋白含量较低，也足以激活靶基因（Goentoro 与 Kirschner，2009）。此外，多种非 TCF 转录因子被认为可作为替代性转录效应分子，但这些结论尚需独立验证。与之相反，近期在哺乳动物细胞（Schuijers 等，2014）和果蝇（Franz 等，2017）中开展的全基因组分析显示，β-连环蛋白靶基因的直接激活均需依赖 TCF 家族蛋白作为最终效应因子。当β-连环蛋白被招募至启动子或增强子区域后，其 C 端转录激活结构域会启动基因转录（van de Wetering 等，1997）。该蛋白还能结合染色质修饰因子如 CBP（参见 Städeli 等 2006 年综述）及 Parafibromin/Hyrax（酵母 Cdc73 的同源蛋白，Mosimann 等 2006）。"

Wnts exert a wide variety of effects on target cells during development. Arguably, the hottest focus of the Wnt field involves its role in healthy stem cells and in cancer. Stem cells-be it embryonic stem (ES) cells or adult stem cells-display the defining capacity to self-renew, while also producing specialized cells. Stem cell fate and behavior are primarily dictated by extrinsic, short-range signals, which typically emanate from the stem cell niche (Losick et al., 2011).
Wnt 信号分子在发育过程中对靶细胞具有广泛多样的调控作用。当前 Wnt 研究领域最热门的焦点无疑是其在正常干细胞和癌症中的功能。无论是胚胎干细胞（ES 细胞）还是成体干细胞，都具有两大关键特征：自我更新能力和分化潜能。研究表明，干细胞的命运决定和行为调控主要依赖于来自干细胞微环境的外源性短程信号（Losick 等人，2011）。

As first proof of the involvement of Wnt in adult stem cell biology, gene disruption of mouse TCF4 lead to loss of intestinal stem cells and the subsequent breakdown of the epithelium (Korinek et al., 1998). Since then, the Wnt pathway has been found to be required for most if not all stem cell types. Thus, the ES phenotype can be maintained in culture by just two small molecules, one being the Wnt activating GSK3 inhibitor CHIR (Silva et al., 2008). Indeed, purified Wnt protein maintains pluripotency of ES cells as well (ten Berge et al., 2011).
首个证明 Wnt 参与成体干细胞生物学的实验显示，破坏小鼠 TCF4 基因会导致肠道干细胞缺失及上皮组织瓦解（Korinek 等，1998）。此后研究发现，Wnt 信号通路对绝大多数（甚至可能全部）干细胞类型都不可或缺。因此，仅需两种小分子——包括激活 Wnt 通路的 GSK3 抑制剂 CHIR（Silva 等，2008），就能在体外培养中维持胚胎干细胞（ES）的特性。更值得注意的是，纯化的 Wnt 蛋白本身也具备维持 ES 细胞多能性的功能（ten Berge 等，2011）。

In the hair follicle, Wnt signaling plays multiple roles in the biology of stem cells and progenitors (DasGupta and Fuchs, 1999; Lim et al., 2016). Blocking Wnt signaling by overexpression of Dkk eliminates hair follicles and other skin appendages, such as the mammary gland (Andl et al., 2002). In the hematopoietic system, overexpressing Axin1 lowers the numbers of transplantable stem cells (Reya et al., 2003). In another approach, treatment of hematopoietic stem cells with isolated Wnt3a protein increases self-renewal, as measured by clonogenic assays and long-term reconstitution in irradiated mice (Willert et al., 2003).
在毛囊中，Wnt 信号通路对干细胞和祖细胞的生物学功能具有多重调控作用（DasGupta 与 Fuchs，1999；Lim 等，2016）。若通过过度表达 Dkk 蛋白阻断 Wnt 信号，会导致毛囊及乳腺等皮肤附属器官的缺失（Andl 等，2002）。在造血系统研究中发现，Axin1 基因的过度表达会显著降低可移植干细胞的数目（Reya 等，2003）。另有研究表明，使用纯化的 Wnt3a 蛋白处理造血干细胞后，能显著增强其自我更新能力——这一结论通过克隆形成实验及辐照小鼠的长期造血重建实验得到验证（Willert 等，2003）。

LGR5 and Axin2 (two stem cell-specific Wnt target genes, themselves encoding Wnt pathway components) have allowed the creation of powerful genetic tools for lineage tracing of a multitude of known and novel adult stem cells. Lgr5 is expressed in small, cycling cells at the base of small intestinal crypts that were observed originally by Paneth (1887) and were later postulated (Cheng and Leblond, 1974) to represent the intestinal stem cells. An Lgr5 locus-specific CreERT2 mouse demonstrated by lineage tracing that the constantly cycling Lgr5 ${}^{+}$${}^{+}$^(+){ }^{+}stem cells are long-lived, multipotent adult stem cells (Barker et al., 2007). Using the same lineage-tracing strategy, Lgr5 was subsequently demonstrated to mark stem cells in many other organs and tissues, including the hair follicle (Jaks et al., 2008), stomach
LGR5 和 Axin2（两种干细胞特异性的 Wnt 靶基因，其本身编码 Wnt 通路相关蛋白）为多种已知及新型成体干细胞的谱系追踪提供了强大的遗传学工具。Lgr5 基因在小肠隐窝基底部的增殖性小细胞中表达，这类细胞最早由 Paneth（1887 年）发现，后经 Cheng 和 Leblond（1974 年）推测为肠道干细胞。通过构建 Lgr5 位点特异性 CreERT2 小鼠并进行谱系追踪，研究证实这些持续增殖的 Lgr5 阳性细胞是具有长期存活能力、多向分化潜能的成体干细胞（Barker 等，2007）。采用相同策略，后续研究进一步发现 Lgr5 还能标记包括毛囊（Jaks 等，2008）和胃在内的多种器官组织中的干细胞
(Barker et al., 2010), pancreas (Huch et al., 2013a), liver (Huch et al., 2013b), kidney (Barker et al., 2012), ovarial epithelium (Ng et al., 2014), inner ear (Chai et al., 2012; Shi et al., 2012), taste buds (Yee et al., 2013), and mammary gland (de Visser et al., 2012; Plaks et al., 2013). In agreement, lineage tracing approaches based on Axin2-CreERT2 and other genes have revealed Wnt-responsive adult stem cell function in the mammary gland (van Amerongen et al., 2012), the interfollicular epidermis (Lim et al., 2013), the quiescent bulge of telogen hair follicles (Lim et al., 2016), the nail (Takeo et al., 2013), and the pericentral region of liver lobules (Wang et al., 2015).
"(Barker 等，2010)的研究表明，胰腺(Huch 等，2013a)、肝脏(Huch 等，2013b)、肾脏(Barker 等，2012)、卵巢上皮(Ng 等，2014)、内耳(Chai 等，2012；Shi 等，2012)、味蕾(Yee 等，2013)以及乳腺(de Visser 等，2012；Plaks 等，2013)中存在此类干细胞。类似地，基于 Axin2-CreERT2 等基因的谱系追踪技术也证实，在乳腺(van Amerongen 等，2012)、毛囊间表皮(Lim 等，2013)、静止期毛囊隆起区(Lim 等，2016)、指甲(Takeo 等，2013)和肝小叶中央静脉周围区域(Wang 等，2015)中，存在对 Wnt 信号响应的成体干细胞功能。"

An organoid can be defined as a 3D structure grown from stem cells and consisting of organ-specific cell types that selforganizes through cell sorting and spatially restricted lineage commitment. Purified Wnt protein was shown to expand the number of clonogenic cells from mammary gland adult stem cells, while retaining the developmental potential of the cells upon transplantation (Zeng and Nusse, 2010). More complete organoids were observed when growth factors cocktails were refined. Based on the observation that the Wnt-dependent Lgr5 crypt stem cells divide 1,000s of times in vivo, a culture system was established that allows growth of epithelial organoids (“mini-guts”) from a single Lgr5 stem cell (Sato et al., 2009). The stem cells are suspended in Matrigel and are stimulated with R-spondin1, complemented with EGF and the BMP inhibitor Noggin. The organoids grow as a simple highly polarized and fully differentiated epithelium, tightly closing off a central lumen, from which crypt-like structures project outward. All cell types of the gut epithelium are represented at normal ratios (Grün et al., 2015; Sato et al., 2009). The organoids can be grown for years and are remarkably stable, both genetically and phenotypically. As proof of this stability, organoids grown from a single murine Lgr5 colon stem cell were transplanted into multiple mice with experimental colitis. The integrated organoids persisted longterm as functional epithelial patches, indiscernible from the surrounding host epithelium (Yui et al., 2012). Addition of small molecule inhibitors of Alk and p38 allowed long-term culture of human small intestine and colon organoids (Jung et al., 2011; Sato et al., 2011). Similar cultures that additionally contained mesenchymal elements could be started from induced pluripotent stem cells (iPSCs) (Spence et al., 2011)
类器官是指由干细胞培育而成的三维结构，其包含特定器官的细胞类型，并通过细胞分选和空间限制性谱系分化实现自我组织。研究表明，纯化的 Wnt 蛋白能够促进乳腺成体干细胞形成克隆细胞群，同时保持这些细胞在移植后的发育潜力（Zeng 和 Nusse，2010 年）。当优化生长因子组合后，可培育出更完整的类器官。基于 Lgr5 隐窝干细胞在体内依赖 Wnt 信号进行数千次分裂的现象，研究人员建立了培养系统，成功实现单个 Lgr5 干细胞发育成上皮类器官（"微型肠道"）（Sato 等，2009 年）。该培养体系将干细胞悬浮于 Matrigel 基质中，使用 R-spondin1 配合 EGF 和 BMP 抑制剂 Noggin 进行刺激。这些类器官发育为高度极化且完全分化的单层上皮结构，形成封闭的中央管腔，并向外延伸出隐窝样突起，完整包含了肠道上皮所有细胞类型且比例正常（Grün 等，2015 年；Sato 等，2009 年）。这类器官可长期培养，并表现出显著的遗传和表型稳定性。例如，源自单个小鼠 Lgr5 结肠干细胞的类器官被成功移植到多只实验性结肠炎模型小鼠体内，证实了其稳定性。 这些整合的类器官能够长期存活，形成功能性的上皮组织斑块，与宿主原有上皮组织难以区分（Yui 等，2012）。通过添加 Alk 和 p38 的小分子抑制剂，实现了人小肠和结肠类器官的长期培养（Jung 等，2011；Sato 等，2011）。而含有间充质成分的类似培养体系，则可以从诱导多能干细胞（iPSCs）建立（Spence 等，2011）。

This culture system has since been adapted to grow organoids from Wnt-dependent adult stem cells from the epithelial compartments of a growing number of mouse and human tissues of ecto-, meso-, and endodermal origin. The essential components are a potent source of Wnt, a potent activator of tyrosine kinase receptor signaling (such as EGF), inhibition of BMP/ TGF- $\beta$$\beta$beta\beta signals, and Matrigel. Thus, organoid protocols have been reported for mouse and human stomach (Barker et al., 2010; Bartfeld et al., 2015; McCracken et al., 2014), liver (Huch et al., 2013b, 2015), pancreas (Boj et al., 2015; Huch et al., 2013a), prostate (Boj et al., 2015; Chua et al., 2014; Huch et al., 2013a; Karthaus et al., 2014), taste buds (Ren et al., 2014), inner ear (McLean et al., 2017), esophagus (DeWard et al., 2014), fallopian tube epithelium (Kessler et al., 2015),
该培养系统经过改良，现已能够利用源自小鼠和人类外胚层、中胚层及内胚层多种组织的上皮区室中依赖 Wnt 信号的成体干细胞培育类器官。其核心培养条件包括：强效 Wnt 信号源、酪氨酸激酶受体信号通路激活剂（如 EGF）、BMP/TGF-β信号抑制因子以及基质胶。目前，已成功建立小鼠和人类多种器官的类器官培养体系，包括胃（Barker 等，2010；Bartfeld 等，2015；McCracken 等，2014）、肝脏（Huch 等，2013b，2015）、胰腺（Boj 等，2015；Huch 等，2013a）、前列腺（Boj 等，2015；Chua 等，2014；Huch 等，2013a；Karthaus 等，2014）、味蕾（Ren 等，2014）、内耳（McLean 等，2017）、食道（DeWard 等，2014）及输卵管上皮（Kessler 等，2015）。

Based on http://web.stanford.edu/group/nusselab/cgi-bin/wnt/human_ genetic_diseases (selected for diseases with multiple pathway components implicated).
数据源自 http://web.stanford.edu/group/nusselab/cgi-bin/wnt/human_ genetic_diseases（筛选标准为涉及多个通路成分的遗传疾病）。
mammary gland (Jamieson et al., 2016), and salivary gland (Maimets et al., 2016; Nanduri et al., 2014).
乳腺（Jamieson 等，2016）和唾液腺（Maimets 等，2016；Nanduri 等，2014）。

The development of potent “surrogate” Wnt proteins greatly facilitates the activation of Wnt receptors in organoid cultures, as the surrogates are not lipid-modified and therefore do not require serum-derived carrier proteins (Janda et al., 2017). Another technical improvement involves the replacement of Ma trigel by a synthetic hydrogel (Gjorevski et al., 2016). It currently appears that most, if not all, mammalian epithelia utilize Wntdependent Axin2/Lgr5 ${}^{+}$${}^{+}$^(+){ }^{+}stem cells for their homeostatic selfrenewal and damage repair, and this, likely in all cases, allows the establishment of culture conditions for long-term organoid growth.
高效“替代型”Wnt 蛋白的研发显著提升了类器官培养中 Wnt 受体的激活效率，由于这类替代蛋白无需脂质修饰，因而摆脱了对血清载体蛋白的依赖（Janda 等，2017）。另一项技术突破是用合成水凝胶取代了 Matrigel 基质（Gjorevski 等，2016）。现有研究表明，绝大多数（甚至可能全部）哺乳动物上皮组织都依赖 Wnt 信号通路的 Axin2/Lgr5 ${}^{+}$${}^{+}$^(+){ }^{+} 干细胞实现稳态更新与损伤修复——这一共性特征使得建立长期类器官培养体系成为可能。

Since Wnt signals are crucial for the activity of epithelial stem cells, it is not surprising that Wnt pathway mutations are frequently observed in carcinomas. The APC gene was first identified by being mutated in a hereditary colon cancer syndrome termed familiar adenomatous polyposis (Kinzler et al., 1991; Nishisho et al., 1991). Similarly, most cases of sporadic colorectal cancer result from loss of both APC alleles (Kinzler and Vogelstein, 1996; Wood et al., 2007). Loss of APC function leads to the inappropriate stabilization of $\beta$$\beta$beta\beta-catenin (Rubinfeld et al., 1996) and the formation of constitutive complexes between $\beta$$\beta$beta\beta-catenin and the intestinal TCF family member TCF7I2/TCF4 (Korinek et al., 1997).
Wnt 信号通路在上皮干细胞活性中起关键作用，因此 Wnt 通路突变在癌症中频繁出现并不意外。APC 基因最初是在家族性腺瘤性息肉病（一种遗传性结肠癌综合征）中因突变而被发现的（Kinzler 等，1991；Nishisho 等，1991）。同样，大多数散发性结直肠癌病例也源于两个 APC 等位基因的缺失（Kinzler 和 Vogelstein，1996；Wood 等，2007）。APC 功能缺失会导致 $\beta$$\beta$beta\beta -连环蛋白异常稳定（Rubinfeld 等，1996），并促使 $\beta$$\beta$beta\beta -连环蛋白与肠道 TCF 家族成员 TCF7I2/TCF4 形成持续性复合物（Korinek 等，1997）。

A growing series of activating mutations in other Wnt pathway components has been reported since in a variety of cancers. Pa-
此后，在多种癌症中陆续发现 Wnt 信号通路其他组分存在一系列激活突变。Pa-
tients with hereditary Axin2 mutations display a predisposition to colon cancer (Lammi et al., 2004). In rare cases of colorectal cancers that are wild-type for APC, the same Axin2 gene is mutated (Liu et al., 2000). Axin1 mutations were first noted in hepatocellular carcinomas (Satoh et al., 2000). In a small, distinct set of colon cancer cases, activating point mutations in $\beta$$\beta$beta\beta-catenin remove the regulatory N -terminal Ser/Thr residues (Morin et al., 1997). Similar $\beta$$\beta$beta\beta-catenin mutations were reported in melanoma (Rubinfeld et al., 1997) and have since been observed in a variety of other carcinomas.
"携带遗传性 Axin2 基因突变的患者易患结肠癌（Lammi 等，2004）。在少数 APC 基因未突变的结直肠癌病例中，同样发现了 Axin2 基因的突变（Liu 等，2000）。Axin1 基因突变最早在肝细胞癌中被报道（Satoh 等，2000）。另有一组特殊的结肠癌病例，其 $\beta$$\beta$beta\beta -连环蛋白发生激活型点突变，导致调控功能的 N 端丝氨酸/苏氨酸残基缺失（Morin 等，1997）。类似的 $\beta$$\beta$beta\beta -连环蛋白突变也见于黑色素瘤（Rubinfeld 等，1997），后续在其他多种癌症中均有发现。"

Most recently, inactivating mutations were first reported in the E3 ligase genes Rnf43 in pancreas cancer (Wu et al., 2011) and Znrf3 in adrenocortical carcinoma (Assié et al., 2014) and subsequently seen in multiple other cancers, adding these two genes to the list of Wnt pathway tumor suppressors. Gene fusions involving R-spondin2 or R-spondin3 are observed in yet another class of rare APC wild-type (WT) colon cancers (Seshagiri et al., 2012). These latter mutations and fusions render the cancer cells highly sensitive to low levels of Wnt, yet (unlike APC, Axin $1/2$$1/2$1//21 / 2, or $\beta$$\beta$beta\beta-catenin mutants) are still ultimately dependent on exogenous Wnts and have been implied to be treatable with inhibitors of Wht secretion or of the FZD/LRP receptor complex (see below).
近期研究发现，E3 泛素连接酶基因 Rnf43 的失活突变最早在胰腺癌中被报道（Wu 等，2011），随后 Znrf3 基因突变在肾上腺皮质癌中被发现（Assié等，2014），并在多种癌症中陆续观察到类似现象，这两个基因因此被纳入 Wnt 信号通路的抑癌基因列表。此外，在另一类罕见的 APC 野生型结肠癌中检测到 R-spondin2/3 基因融合（Seshagiri 等，2012）。这类突变和融合使癌细胞对微量 Wnt 信号异常敏感，但其（不同于 APC、Axin 或β-catenin 突变体）仍完全依赖外源性 Wnt 配体，提示可通过抑制 Wnt 分泌或阻断 FZD/LRP 受体复合物进行治疗（详见下文）。

The link between Wnt-driven stem cells and carcinogenesis is reinforced by reports that demonstrate a link between Wnt signal strength, stem cell signature, and colon cancer stem cell behavior (Merlos-Suárez et al., 2011; Vermeulen et al., 2010; Tammela et al., 2017).
多项研究证实了 Wnt 信号强度、干细胞特征与结肠癌干细胞行为之间的关联（Merlos-Suárez 等，2011；Vermeulen 等，2010；Tammela 等，2017），这进一步强化了 Wnt 驱动型干细胞与肿瘤发生之间的密切联系。

There are many degenerative genetic diseases caused by mutations in Wnt signaling components, either at the somatic cell level or with an inherited component. Table 1 lists various diseases and the Wnt pathway-associated genes that are mutated. Among these are genetic cases where multiple different Wnt signaling components are involved in the same disease, including abnormalities in bone density, tooth development, and the retina. The best-known disorders are mutations in the SOST and LRP6 genes causing sclerosteosis and hereditary osteoporosis (Baron and Kneissel, 2013). Another example of the involvement of multiple Wnt components comes from the retina, where disorders such as familial exudative vitreoretinopathy can be caused by mutations in LRP5, FZD4, or Norrin (Table 1).
Wnt 信号通路组分的突变可导致多种退行性遗传疾病，这些突变可能源于体细胞或具有遗传性。表 1 列举了相关疾病及其对应的 Wnt 通路基因突变。值得注意的是，某些遗传性疾病会同时涉及多个 Wnt 信号组分异常，表现为骨密度异常、牙齿发育障碍及视网膜病变等。其中最典型的当属 SOST 和 LRP6 基因突变引发的硬化性骨化症与遗传性骨质疏松症（Baron 与 Kneissel，2013）。视网膜疾病方面，家族性渗出性玻璃体视网膜病变就是一个典型案例，该病可由 LRP5、FZD4 或 Norrin 基因突变导致（见表 1）。
The nature of these mutations not only illuminates the relevance of the pathways for human health, it also sheds light on the mechanisms of signaling. For example, patients with hereditary abnormal high bone mass carry specific mutations in the LRP5 extracellular domain (Boyden et al., 2002), that generate the receptor refractory to binding of the antagonists SOST and DKK1 (Ellies et al., 2006; Chu et al., 2013). In this case, mapping the sites of the mutations suggested locations of protein interactions. A striking example of how genetics inform Wnt pathway understanding comes from Robinow syndrome. This inherited disease, affecting the skeleton in addition to other parts of the body, is associated with mutations in three different Wnt signaling components: Wnt5a, ROR2 (van Bokhoven et al., 2000), and DVL1 (Table 1).
这些突变不仅揭示了相关通路对人类健康的重要意义，还阐明了信号传导的具体机制。以遗传性异常高骨量患者为例，其 LRP5 基因的细胞外结构域存在特定突变（Boyden 等，2002），这些突变导致受体无法与拮抗剂 SOST 和 DKK1 结合（Ellies 等，2006；Chu 等，2013）。通过定位这些突变位点，研究人员得以推断出蛋白质相互作用的关键区域。Robinow 综合征是遗传学研究推动 Wnt 通路理解的典型案例。这种遗传性疾病除影响骨骼发育外，还累及身体其他部位，其发病与 Wnt 信号通路中三个关键组分——Wnt5a、ROR2（van Bokhoven 等，2000）和 DVL1（表 1）的突变密切相关。

What can we learn from these disease implications, and can therapies be designed based on Wnt signaling mechanisms?
我们可以从这些疾病影响中汲取哪些经验？能否基于 Wnt 信号传导机制来设计治疗方案？

Based on http://web.stanford.edu/group/nusselab/cgi-bin/wnt/smallmolecules.
来源：http://web.stanford.edu/group/nusselab/cgi-bin/wnt/smallmolecules。

In considering a widely used pathway such as Wnt as a target for intervention, a concern arises from the predicted side effects of drugs (Kahn, 2014). In the case of Wnt signaling, however, one of the components, SOST, provides a unique target in bone diseases, including osteoporosis. SOST, one of the negative regulators of Wnt, is expressed in the bone only and has phenotypes limited to the bone tissue. This suggests that blocking SOST would only impact on bone (Jawad et al., 2013), and indeed, an antibody targeting SOST, known under the brand name Romosozumab, has yielded encouraging results in clinical trials (Cosman et al., 2016).
在考虑将 Wnt 这类广泛应用的信号通路作为干预靶点时，药物可能产生的副作用令人担忧(Kahn, 2014)。但就 Wnt 信号通路而言，其负调控因子 SOST 具有组织特异性——仅在骨骼中表达，且表型局限于骨组织，这使其成为治疗骨质疏松等骨疾病的理想靶点。研究表明，抑制 SOST 仅会影响骨骼功能(Jawad et al., 2013)。实际上，靶向 SOST 的单抗药物 Romosozumab 已在临床试验中展现出显著疗效(Cosman et al., 2016)。

With respect to other possible targets, extensive efforts have been made to block Wnt signaling with small molecules, facilitated by sensitive and quantitative Wnt reporters (Table 2). The most effective target in the case of cancer would be the complex between TCF and $\beta$$\beta$beta\beta-catenin, as it mediates signaling at a downstream node in the pathway, but despite numerous efforts, this target has proven to be elusive. The screens have, however, led to compounds that impact the stability of Axin, which is regulated by tankyrase-mediated ADP-ribosylation. Molecules such as IWR (Lu et al., 2009) and XAV939 (Huang et al., 2009) inhibit tankyrase, thereby increasing Axin levels and lowering $\beta$$\beta$beta\beta-catenin to inhibit Wnt signaling (Kulak et al., 2015). At other levels of Wnt signaling, very specific and useful inhibitors have been found to block Porcupine, the enzyme catalyzing the acylation of Wnt proteins (Table 2). These molecules include IWP2, C59, and LGK974, all inhibiting Porcupine and thereby leading to a block in Wnt secretion, as acylation is required for Wnt transport (Lu et al., 2009). In cancers that are the consequence of $\beta$$\beta$beta\beta-catenin/ APC mutations, it is unlikely that interfering with Wnt would have a significant effect on the growth of the tumors. On the other hand, there is substantial evidence that the outgrowth of metastatic lesions and cancer stem cells is promoted by Wnts themselves (Malladi et al., 2016; Nguyen et al., 2009; Yu et al., 2013; Tammela et al., 2017), suggesting that Porcupine targeting
针对其他潜在靶点，研究人员已利用高灵敏度、定量化的 Wnt 报告系统（表 2），开展了大量小分子阻断 Wnt 信号通路的研究。对于癌症治疗而言，TCF 与β-连环蛋白（ $\beta$$\beta$beta\beta -catenin）形成的复合物是最具潜力的靶点——该复合物在信号通路下游起关键调控作用。然而尽管多方尝试，这一靶点仍难以有效干预。不过相关筛选工作已发现：通过抑制 tankyrase 介导的 ADP 核糖基化来稳定 Axin 蛋白的化合物（如 IWR 和 XAV939），可提升 Axin 水平并降低β-连环蛋白（ $\beta$$\beta$beta\beta -catenin）含量，从而抑制 Wnt 信号（Kulak 等，2015）。在 Wnt 通路的其他环节，研究者还发现了能特异性抑制 Porcupine 酶（催化 Wnt 蛋白酰基化）的高效抑制剂（表 2），包括 IWP2、C59 和 LGK974 等。这些化合物通过阻断 Wnt 蛋白必需的酰基化修饰，有效抑制其分泌（Lu 等，2009）。值得注意的是，对于由β-连环蛋白（ $\beta$$\beta$beta\beta -catenin）/APC 基因突变引发的癌症，干扰 Wnt 信号通路可能对肿瘤生长影响有限。 "另一方面，大量研究表明，Wnts 本身会促进转移病灶和癌症干细胞的生长（Malladi 等，2016；Nguyen 等，2009；Yu 等，2013；Tammela 等，2017），这提示 Porcupine 靶向治疗"
drugs could be beneficial. In promising experiments, some of these drugs have been shown to inhibit the growth of transplanted or even autochthonous tumors in mouse models (Madan et al., 2016; Tammela et al., 2017) and a clinical trial for the Porcupine inhibitor LGK974, in patients with several forms of cancer, is ongoing (https://clinicaltrials.gov/ct2/show/NCT01351103).
这些药物可能具有疗效。在颇具前景的实验中，部分药物已证实能抑制小鼠模型中移植瘤乃至原位瘤的生长（Madan 等，2016；Tammela 等，2017）。目前，针对 Porcupine 抑制剂 LGK974 的临床试验正在多种癌症患者中开展（临床试验编号：NCT01351103，详见 https://clinicaltrials.gov/ct2/show/NCT01351103）。

The possible requirement for Wnt ligands in cancer cell proliferation also boosts hope for intervention at the receptor level, and there are promising leads in this area. A recent example comes from genetic screens for mutations that sensitize pancreatic tumor cells that are mutant for RNF43 (RNF43 mutations make these cells dependent on Wnt ligand). Among the mutation suppressing the RNF43 growth phenotype were several in FZD5, indicating that the tumor cells are dependent on Wnt-FZD signaling. As a follow-up, it was shown that the growth of these tumors was attenuated by antibodies directed at FZDs (Steinhart et al., 2017). Similarly, a monoclonal antibody (OMP-18R5) that binds to several FZD family members inhibits the growth of several tumors in xenograft studies, while antibodies that are raised against R -spondins cause the differentiation of colon tumor cells and loss of stem cell function (Storm et al., 2016).
Wnt 配体在癌细胞增殖中的潜在作用，为受体层面的干预带来了希望，目前该领域已取得一些突破性进展。例如，近期一项针对 RNF43 突变型胰腺肿瘤细胞（此类突变导致细胞依赖 Wnt 配体）的遗传筛选发现，FZD5 基因的多个突变能抑制 RNF43 相关的生长表型，证实肿瘤生长依赖于 Wnt-FZD 信号通路。后续实验证明，靶向 FZD 受体的抗体可显著抑制这类肿瘤的生长（Steinhart 等，2017）。此外，能结合多种 FZD 家族成员的单克隆抗体 OMP-18R5 在异种移植模型中显示出广谱抗肿瘤效果，而针对 R-spondins 的抗体则可诱导结肠癌细胞分化并使其丧失干细胞特性（Storm 等，2016）。
In addition to blocking Wht signaling, clinical value could also emerge from stimulating the pathway for tissue regeneration. The Wnt protein itself is problematic for use as a drug because of its hydrophobicity and because of complications in producing significant quantities. Recently, however, soluble Wnt protein agonists have been shown to activate Wnt signaling in vivo (Janda et al., 2017). In addition, several small molecule compounds (L807mts, Bio, CHIR, and SB-216763) (Licht-Murava et al., 2016) interfere with GSK3 and thus induce Wnt target gene expression. There is hope that these drugs are of use in treating neurodegenerative disorders, including Alzheimer’s disease (Licht-Murava et al., 2016). Mechanistically, the effect of GSK3 inhibitors in the CNS could be mediated by the Wnt target gene REST, which acts as a is a repressor of neuronal genes
除了抑制 Wnt 信号通路外，激活该通路促进组织再生同样具有潜在临床应用价值。由于 Wnt 蛋白存在疏水性强、难以规模化生产等问题，其直接作为药物使用面临挑战。不过最新研究表明，可溶性 Wnt 蛋白激动剂能够在活体内有效激活 Wnt 信号通路（Janda 等人，2017）。另有多种小分子化合物（如 L807mts、Bio、CHIR 和 SB-216763）可通过抑制 GSK3 活性来上调 Wnt 靶基因表达（Licht-Murava 等人，2016）。这类药物在治疗阿尔茨海默病等神经退行性疾病方面展现出应用前景。从作用机制来看，GSK3 抑制剂在中枢神经系统的作用可能依赖于 Wnt 通路靶基因 REST——该基因能够抑制神经元相关基因的表达。
during embryonic development and has been shown to be protective in Alzheimer’s disease (Lu et al., 2014).
在胚胎发育阶段，该物质已被证实对阿尔茨海默病具有防护作用（Lu 等，2014）。

In conclusion, we are now at a point in the history of Wnt signaling where the implications of this pathway for understanding disease are coming into focus. The efforts in finding ways to interfere with Wnt signaling are still at an early stage, but there are promising leads that hopefully will translate soon into real therapies.
综上所述，在 Wnt 信号通路研究的历史进程中，我们已到达一个关键节点——该通路对疾病机制的揭示正逐渐明朗。尽管目前针对 Wnt 信号通路的干预研究尚处初级阶段，但已有若干突破性进展，这些成果有望在短期内转化为切实有效的治疗方案。

We thank Dr. Vivian Li for contributions to the figures. The authors are supported by the Howard Hughes Medical Institute (R.N.), the European Union, and the Cancer Genomics.nl program (H.C.).
我们感谢 Vivian Li 博士为图表绘制做出的贡献。本研究得到了霍华德·休斯医学研究所（R.N.）、欧盟以及 Cancer Genomics.nl 项目（H.C.）的资助支持。

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