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The Advantages and Disadvantages of Sfrp1 and Sfrp2 Expression in Pathological Events

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The Advantages and Disadvantages of Sfrp1 and Sfrp2 Expression in Pathological Events Tohoku J. Exp. Med., 2010, 221, 11-17 Sfrp1/2 in Deseases 11 Invited Review for the 90th Anniversary The Advantages and Disadvantages of Sfrp1 and Sfrp2 Expression in Pathological Events Pilar Esteve1 and Paola Bovolenta1 1Departamento de Neurobiología Molecular, Celular y del Desarrollo, Instituto Cajal (CSIC) and CIBER de Enfermedades Raras (CIBERER), Madrid, Spain Secreted Frizzled Related Proteins (Sfrps) are a family of secreted proteins that can bind both to Wnt ligands and Frizzled receptors, thereby modulating the Wnt signalling cascades. Recent studies have shown that Sfrps can also interact with Wnt unrelated molecules such as RANKL, a member of the tumor necrosis factor family, Tolloid metalloproteinases or integrin-fibronectin complexes. Alterations in the levels of Sfrp expression have been recently associated with different pathological conditions, including tumor formation and bone and myocardial disorders. Here, we summarise the evidence that relates Sfrps with these diseases and discuss how the proposed multiple Sfrp interactions with Wnt related and unrelated pathways may explain their implication in such diverse pathologies. Keywords: Secreted Frizzled Related Protein; Wnt signalling; cancer; bone repair; myocardium Tohoku J. Exp. Med., 2010, 221 (1), 11-17. © 2010 Tohoku University Medical Press Secreted Frizzled Related Proteins (Sfrps) were tissue homeostasis (Nusse 2005). Its wide variety of actions initially and independently identified as soluble factors is achieved by the combinatorial use of 19 distinct Wnt implicated in early embryonic development (Leyns et al. ligands and of different classes of receptors and coreceptors, 1997; Wang et al. 1997) and as modulators of apoptotic which activate at least three partially independent transduc- events (Melkonyan et al. 1997). This protein family, which tion cascades (van Amerongen and Nusse 2009). It seems counts with five members in mammals, received this name thus reasonable that modulators of Wnt signaling, such as because their N-terminal region shows a remarkable Sfrps (Bovolenta et al. 2008), should have similar intricate sequence homology with the extracellular Wnt binding interactions with both Wnt and Fz. However, to make domain of Frizzled receptors (Hoang et al. 1996; Leyns et matters worse, Sfrps have been shown to interact also with al. 1997; Lin et al. 1997; Wang et al. 1997). Initial studies, molecules unrelated to Wnts. For example, Sfrp1 binds to using Xenopus embryos as a model, demonstrated that frzb and inhibits the activity of RANKL, a member of the TNF (Sfrp3), the first isolated member of the family, bound Wnt family involved in osteoclast formation (Hausler et al. ligands and prevented canonical Wnt signalling activation, 2004). Sfrp2 specifically binds to Tolloid metalloproteinases pointing to a Wnt antagonist function based on ligand and thereby regulates procollagen processing (Kobayashi et sequestration (Kawano and Kypta 2003). This relatively al. 2009) or interacts with an integrin-fibronectin complex simple scenario was complicated by subsequent studies modulating apoptosis (Lee et al. 2004), while Sfrp3 binds to showing that Sfrps can inhibit non-canonical signalling EGF blocking its function in different cell contexts (LaMonica et al. 2009; Matsuyama et al. 2009; Sugiyama et (Scardigli et al. 2008). al. 2010) either by binding to Fz receptors, activating an A possible explanation for this variety of interactions intracellular signal (Rodriguez et al. 2005; Dufourcq et al. may reside in the structure of these proteins, which are 2008; Kawano et al. 2009) or by enhancing Wnt diffusion in composed of two independently folded domains. The the extracellular space, consequently expanding their signal- Cysteine Rich Domain (CRD) at the N-terminus, shares ling range (Mii and Taira 2009). Thus, context-dependent similarities with the extracellular domain of transmembrane interactions among different Wnt, Sfrps and Fz molecules proteins including, as mentioned above, Fz receptors, the seem to modulate the intricate Wnt signalling cascade in Shh transducer Smoothened and the Wnt receptor tyrosine both a positive and negative way (Fig. 1). kinases RORs (Roszmusz et al. 2001). The C-terminal Wnt signaling is probably one of the most extensively domain contains a Netrin-Related motif (NTR) defined, in used cell-cell communication pathway in development and the most closely related Sfrp1/2/5, by six cysteine residues Received March 4, 2010; revision accepted for publication March 26, 2010. doi:10.1620/tjem.221.11 Correspondence: Pilar Esteve and Paola Bovolenta, Departamento de Neurobiología Molecular, Celular y del Desarrollo, Instituto Cajal (CSIC) and CIBER de Enfermedades Raras (CIBERER), Avda. Dr. Arce 37, Madrid 28002, Spain. e-mail: [email protected] or [email protected] 11 12 P. Esteve and P. Bovolenta Fig. 1. Multifunctional molecular interactions of Sfrp1/2 and their implication in pathological events. The drawing depicts possible mechanisms of action of Sfrp1/2 and their implications in pathological events. A) Sfrp1 and Sfrp2 sequester Wnts, thereby antagonize Wnt/βcatenin signaling. B) Frzb (Sfrp3) and Crescent favor the diffusion of Wnts, enhancing their signaling range. C) Sfrp1 and Sfrp2 bind to Fz receptors activating intracellular signals. D) Sfrp1 binds to RANKL preventing interaction with the RANK receptor. E) Sfrp2 binds to and enhances the procollagen proteinase activity of BMP1/ Tolloid-like metallo-proteinases, accelerating the processing of pro-collagen. F) Sizzled binds to and inhibits the Chordinase activity of BMP1/ Tolloid-like metalloproteinases. Unprocessed Chordin binds and sequesters BMPs. that form three disulfide bridges. This motif characterises a of CpG islands causes gene silencing and is considered one number of unrelated proteins including Netrin-1, tissue of the most frequent epigenetic alterations associated with inhibitors of metalloproteinases (TIMPs), complement cancer in humans (Esteller 2005a, 2005b). Numerous genes proteins and TypeI procollagen C-proteinase enhancer became hypermethylated and silenced in different type of proteins (PCOLCEs) (Banyai and Patthy 1999). cancers but Sfrp1 and Sfrp2 hypermethylation seems to Although it was initially shown that the CRD domain occur from the very beginning in basically all tumour types, of Sfrps is necessary and sufficient for Wnt binding (Lin et including breast (Zhou et al. 1998; Turashvili et al. 2006; al. 1997; Bafico et al. 1999), subsequent studies demon- Suzuki et al. 2008), gastric (To et al. 2001), cervix (Ko et al. strated that the CRD domain also interact with Fz and 2002), hepatocellular (Huang et al. 2007), pancreas (Bu et Tolloid-like metalloproteases (Lee et al. 2006; Lopez-Rios al. 2008), lung (Fukui et al. 2005), ovary (Takada et al. et al. 2008; Kobayashi et al. 2009) while the NTR domain 2004), renal (Dahl et al. 2007; Gumz et al. 2007), prostate can tightly bind to Wnt ligands independently of the (Lodygin et al. 2005) and colon (Suzuki et al. 2002; presence of the CRD domain (Uren et al. 2000; Lopez-Rios Caldwell et al. 2004; Suzuki et al. 2004) carcinomas, as et al. 2008), supporting the context dependent functions well as in non-solid tumours like myeloid leukaemias (Jost observed for Sfrps. et al., 2008) or myelomas (Jost et al. 2009). The correlation Below we discuss how this variety of possible Sfrps between cancer and loss of Sfrp1 expression is so strong interactions may explain their implication in unrelated that, at least for bladder carcinomas (Stoehr et al. 2004; pathological processes such as cancer, bone or myocardial Urakami et al. 2006), it has been proposed that the status of diseases. We will focus on Sfrp1 and Sfrp2, since these are Sfrp1 promoter methylation could serve as an epigenetic the family members, which received most attention. biomarker for cancer detection and progression, where hypermethylation will be associated with unfavourable Sfrp1 and Sfrp2 generally protect prognosis (Lee et al. 2004; Veeck et al. 2006). from carcinogenesis In line with these epigenetic studies, a large-scale anal- The suppression or down-regulation of Sfrp1 and Sfrp2 ysis in tumours derived from a total of 36 organs demon- expression seems to be a key event in the onset of tumour strated a complete loss of Sfrp1 expression in 82% of the formation. In addition to somatic mutations, epigenetic analysed samples (Dahl et al. 2007). Deletion of the chro- DNA alterations play crucial roles in tumorigenesis (Baylin mosomal region 8p12-p11.1 comprising the SFRP1 locus and Herman 2000; Feinberg and Tycko 2004). Methylation has been also reported in a few cancer cases (Ugolini et al. of gene promoter regions enriched in CpG dinucleotides 1999; Stoehr et al. 2004; Dahl et al. 2007). A tempting (CpG islands) is among the epigenetic modifications that speculation from these studies is that Sfrp1, and possibly controls the levels of gene transcription. Hypermethylation the related Sfrp2, act as tumour suppressor genes (Lee et al. Sfrp1/2 in Deseases 13 2004; Veeck et al. 2006) and their silencing may predispose together with the local availability of Fz, Wnts and down- to neoplastic progression (Wong et al. 2002). Supporting stream signalling components- including those of the non this possibility, forced Sfrp1 re-expression in breast (Suzuki canonical pathway (Katoh 2005)- should be major determi- et al. 2008; Matsuda et al. 2009), hepatocellular (Shih et al. nants in the onset and progression of carcinogenesis (Uren
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