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Dickkopf Proteins and Their Role in Cancer: a Family of Wnt Antagonists with a Dual Role

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Dickkopf Proteins and Their Role in Cancer: a Family of Wnt Antagonists with a Dual Role pharmaceuticals Review Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role Irina Giralt 1,†, Gabriel Gallo-Oller 1,† , Natalia Navarro 1, Patricia Zarzosa 1 , Guillem Pons 1 , Ainara Magdaleno 1, Miguel F. Segura 1 , José Sánchez de Toledo 1, Lucas Moreno 1,2, Soledad Gallego 1,2 and Josep Roma 1,* 1 Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; [email protected] (I.G.); [email protected] (G.G.-O.); [email protected] (N.N.); [email protected] (P.Z.); [email protected] (G.P.); [email protected] (A.M.); [email protected] (M.F.S.); [email protected] (J.S.d.T.); [email protected] (L.M.); [email protected] (S.G.) 2 Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain * Correspondence: [email protected]; Tel.: +34-934894067 † Both authors contributed equally. Abstract: The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Citation: Giralt, I.; Gallo-Oller, G.; Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of Navarro, N.; Zarzosa, P.; Pons, G.; Magdaleno, A.; Segura, M.F.; Sánchez antagonist proteins. Although there is growing information related to function and regulation of de Toledo, J.; Moreno, L.; Gallego, S.; Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been et al. Dickkopf Proteins and Their fully developed. This review provides an update on the role of DKK proteins in cancer and possible Role in Cancer: A Family of Wnt potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or Antagonists with a Dual Role. clinical trials are also reviewed. Pharmaceuticals 2021, 14, 810. https://doi.org/10.3390/ph14080810 Keywords: Wnt signaling; Wnt antagonists; Dickkopf; DKK Academic Editor: Carlo Marchetti Received: 19 July 2021 1. Overview of the Wnt Pathway Accepted: 14 August 2021 Published: 18 August 2021 The Wnt signaling pathway is a highly conserved pathway involved in many pro- cesses of embryonic development such as proliferation, differentiation and epithelial- Publisher’s Note: MDPI stays neutral mesenchymal transition in a wide range of tissues. During the early stages of embryoge- with regard to jurisdictional claims in nesis, the Wnt pathway plays a crucial role in body–axis formation. Later, this pathway published maps and institutional affil- is needed for the development of many organs such as brain, kidney, reproductive tract iations. and mammary glands, among others [1]. The pathway can be activated in a canonical or non-canonical manner. The canonical pathway is β-catenin-dependent and requires the binding of Wnt ligands to receptors [2]. The first step involves the Wnt ligands, Frizzled (Fz) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Wnt ligands are Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. secreted and bind to Fz. LRP5/6 co-receptors are necessary for mediating Wnt signaling. This article is an open access article In an “ON” state (Figure 2A), the interaction Wnt-Fz-LRP5/6 activates the disheveled distributed under the terms and protein (Dsh) (in humans encoded by DVL1 gene), which plays a role as a key switch for conditions of the Creative Commons Wnt signaling. Dsh constitutes an element which, depending on the context, can activate Attribution (CC BY) license (https:// different downstream effectors and modify the response. The main function of Dsh is creativecommons.org/licenses/by/ to inhibit the β-catenin destruction complex. This complex comprises the interaction of 4.0/). adenomatosis polyposis coli (APC), glycogen synthase kinase 3 (GSK3), casein kinase 1 Pharmaceuticals 2021, 14, 810. https://doi.org/10.3390/ph14080810 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 810 2 of 18 alpha (CK1α) and axin. The inactive complex permits the accumulation of β-catenin in cytoplasm to further translocate it to the nucleus. Nuclear β-catenin interacts with T-cell factor/lymphoid enhancer factors (TCF/LEF, transcription factors), and the co-activators CREB-binding protein (CBP) and P300. As a result, the transcription of Wnt target genes is activated [2,3]. Target genes include c-Myc, cyclin D1, axin2, CD44 and c-Jun, among others [4–6]. In an “OFF” state (Figure 2B), there is no binding of Wnt ligands and the destruction complex is active. In this state, CK1α and GSK3 phosphorylate β-catenin, thereby producing its ubiquitination and degradation by E3 ubiquitin ligases [2]. The non-canonical Wnt pathway is β-catenin-independent and can activate additional pathways. Although the non-canonical pathway is under study and not yet well under- stood, it can be classified in two groups: the planar cell polarity pathway and the Wnt/Ca2+ pathway (for a general overview of the non-canonical Wnt, see [7], for Wnt/planar cell polarity [8] and for Wnt/Ca2+ pathway [7]). Activation of the non-canonical pathways also involves the binding of Wnt ligands to the Fz receptor, but independently of the LRP5/6 co-receptor. The non-canonical pathway highlights the complexity and tight regulation of Wnt signaling, providing a large number of receptor/ligand combinations and several layers of regulation, which render this pathway highly context-specific and underline its participation in different cellular responses and diseases [2,3]. It is clear that Wnt signaling plays a pivotal role in developmental and cellular pro- cesses such as cell proliferation, migration and fate determination. However, its dereg- ulation has been identified as a key mechanism in different diseases including cancer. Several aberrant regulatory processes such as mutations, overexpression and downregula- tion mechanisms have been described for members of the Wnt signaling [9]. Among the proteins involved in these mechanisms, some have been described as antagonists of the Wnt pathway. They are usually classified in different families/groups (Table1) and are able to modulate Wnt signaling at 3 levels: Wnt ligands, LRP proteins and/or Fz receptors. Herein, we will focus on the Dickkopf (DKK) family with emphasis on cancer, and current inhibitors/activators under development for this particular Wnt antagonist family will be also reviewed. Table 1. Antagonist proteins of the Wnt signaling pathway. Name Human Gene(s) Protein(s) Inhibited Main Cellular Location WIF1 WIF1 Wnt Extracellular Cerberus CER1 Wnt Extracellular Tiki family TIKI (1–2) Wnt Transmembrane sFRP family sFRP (1–5) Wnt and Fz Extracellular APCDD1 APCDD1 Wnt and LRP Transmembrane DKK family DKK (1–4) LRP Extracellular SOST/Sclerostin SOST LRP Extracellular Wise SOSTDC1 LRP Extracellular MESD MESD LRP Endoplasmic reticulum Waif TPBG LRP Transmembrane IGFBP-4 IGFBP4 LRP and Fz Extracellular Shisa family SHISA (2–9) Fz Transmembrane 2. The Dickkopf (DKK) Family and Its Role in Cancer DKK is a family of soluble (mainly extracellular) LRP5/6 antagonists that prevent the formation of the Fz-LRP6 complex. In the absence of DKKs, the Wnt ligands form a ternary complex with Fz and Lrp5/6, which promotes stabilization of β-catenin, thereby activating the pathway. However, the binding of DKK to Kremen (a family of two transmembrane proteins characterized by their kringle domain) enable the formation of a three-component Pharmaceuticals 2021, 14, 810 3 of 18 Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 18 complex with LRP5/6, which leads to rapid endocytosis and removal of this protein from fromthe plasma the plasma membrane. membrane. The The inhibitory inhibitory function function of DKK of DKK proteins proteins depends depends on theon the presence pres- enceof the of appropriate the appropriate Kremen Kremen proteins proteins [10]. [10]. InIn humans, humans, four four DKKDKK genesgenes have have been been reported: reported: DKK-1DKK-1, ,DKK-2DKK-2, ,DKK-3DKK-3 andand DKK-4DKK-4, , withwith DKK-1DKK-1 beingbeing the the most most studied and characteri characterizedzed [11,12]. [11,12]. DKK DKK proteins proteins show show little little sequencesequence similarity similarity (Figure (Figure 11).). FigureFigure 1. 1. DomainDomain structure structure of of human human DKK DKK protein protein fam family.ily. Cysteine-rich Cysteine-rich domain domain 1 1 (Cys1) (Cys1) and and Cys2 Cys2 domainsdomains are are shared shared by by the the four four members members of ofDKK DKK family. family. Signal Signal peptide, peptide, coiled-coil coiled-coil region region and gly- and cosylationglycosylation sites sites are also are also shown. shown. OnlyOnly two two cysteine-rich cysteine-rich domains domains are are highly highly preserved preserved among among all all the the family family members: members: 1)(1) the the N-terminal N-terminal cysteine-rich cysteine-rich domain domain (formerly (formerly called called Cys1) Cys1) that is that unique is unique for the for mem- the bersmembers of DKK of family; DKK family; and 2) andthe C-terminal (2) the C-terminal cysteine-rich cysteine-rich domain (or domain Cys2) (orwhich Cys2) has which a 10- cysteinehas a 10-cysteine pattern. The pattern. Cys2 Thedomain Cys2 is domainresponsible is responsible for LRP6 binding for LRP6 and binding further and Wnt further inhi- bition,Wnt inhibition, whereas the whereas Cys1 domain the Cys1 modulates domain modulates this interaction. this interaction. Nevertheless, Nevertheless, this described this functiondescribed for function Cys1 appears for Cys1 to appears be functional to be functional only in DKK-1 only in[12].
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