The Wnt Signalling Pathway Glycoprotein Family Biology Essay

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The Wnt proteins belong to a glycoprotein family whose function is important during embryonic development and fetal growth as well as tissue maintenance. The Wnt is a family of encoded glycoproteins constituted of 22 or 24 Cys-residues. The Wnt family has 19 functional members that interact in numerous developmental processes such as embryonic development and adult tissue organ maintenance. In this paper, we describe the role of Wnt signaling during embryonic development and the lack or poor Wnt signaling in adult tissues. We will also describe the molecular pathway mechanism and signaling pathway function during for carcinoma development, and the role of Frizzled receptors (Fz) during the canonical and non canonical pathways used by Wnt signaling.

Introduction

Intercellular signaling pathways are the key element for any multicellular organism."During embryonic development, only a few signaling pathways and specific receptors appear repeatedly in different contexts to regulate cell fate" (2008b; Katoh, 2007)."During adulthood, several signaling pathways are added to the existing pathways which are used for maintenance of organs and regeneration of tissues" (2008a)."The lack of regulation of these signaling pathways during embryonic formation causes aberrant formation; likewise, in adulthood, it causes carcinoma cell formation" (Bruder et al., 2007). Therefore, signaling pathway regulation is necessary for normal cell fate and development. The "Wnt family and Sonic hedgehog signaling are involved in regulating many aspects of development and cell maintenance, which is achieved through a series of signaling pathways" (2008a).

The Wnt family is involved in different processes during embryonic development; therefore, the loss of this protein results in malformation of tissue and tumor formation. Studies showed that mutations in Wnt signaling pathway cause carcinoma development. For example, 90% of colorectal cancer is generated by the loss of Wnt activity (Albuquerque et al., 2010). Loss of Wnt signaling pathway affects in small percentage the formation of other types of carcinomas such as hepatocellular carcinoma and breast cancer (Katoh, 2008). Paradoxically, the Wnt family is hardly ever involved during carcinogenic formation. The consequence of mutation in the Wnt family is the gathering of ?-catenin in the nucleus (Katoh, 2007; Maiese et al., 2008). The ?-catenin is accumulated with its transcription factors and enhancers. Recent data has shown that the genetic functions of the ?-catenin/TCF transcription sites are to control cellular proliferation and repression of some genes during embryogenesis, carcinogenic formation, and post-embryonic regulation of cell positioning (2008b).

The human WNT family is a conserved family of secreted molecules, which regulates cell fate, controls embryogenesis, proliferation and migration. The Wnt family is composed of 19 glycoproteins with 22 or 24 Cys residues (DasGupta et al., 2005; Pleasure, 2001). Molecular changes in WNT gene components lead to aberrant embryonic development as well as human diseases (Tennis et al., 2007). Not only do molecular changes can cause malformations, but also poor or weak regulation of the signaling can cause similar deformation in embryos and adult tissues, i.e., a weak Wnt signaling in adult tissue can initiate carcinoma formation (Van Scoyk et al., 2008; Zhang et al., 2009).

The Wnt family members bound cell surface receptors called Frizzleds (Fz) and various co-receptors such as lipoprotein receptor-related protein (LPR), receptor-like tyrosine kinase (RYK), and tyrosine-protein"kinase transmembrane receptor (ROR2) (2008b). These individual complexes bind also numerous cytoplasmic messengers to activate or initiate intracellular signaling and transduction (Pleasure, 2001) of ?-catenins (Rabelo Fde et al., 2010). Based on biological function, Wnt family is subdivided in various sub classes. For example, some Wnt are specialized in cell proliferation and polar migration, whereas others regulate cell fate specification (Maiese et al., 2008). In general, Wnt members are involved in two kinds of signaling pathways to start ?-catenin transduction (2008b). For example, the canonical signaling pathway or ?-catenin dependent which is used for cell fate determination and the"non-canonical signaling pathway that is used for cell movement and cellular polar migration."

The Wnt signaling components

The term Wnt came from the fusion of two orthologuos genes: Wingless (Wg), a Drosophila segment polarity gene [5], and Int-1, a mouse protooncogene [6, 7] (DasGupta et al., 2005). Wnt family plays an important function on cell fate specification, asymmetric division, cell elongation and proliferation as well as temporal and definitive distribution of cells (2008b; Katoh, 2007; Katoh, 2008). The Wnt signaling begins its functions by binding a Frizzled family molecule (Fz) and the lipoprotein co-receptor LRPs-5 or LRP6 (2008a; Maiese et al., 2008). The canonical pathway is only mediated when Fz and LRP bind with Wnt. Most Wnt proteins bind Fz family proteins and viceversa (Logan and Nusse, 2004).

Once Wnt has bound with Fz and LRP proteins, the complex is translocated to the membrane where the complex interacts with other proteins enambling them to bind only with the LRPs domains (2008a; 2008b; Katoh, 2007). For example, a LRP5 knock down destabilizes auxin binding. This axin destabilization generates a ?-catenin refractory degradation in the cytoplasm and translocate into the nucleus (Katoh, 2007). In the nucleus, it activates TCF/LEF target genes. The result of Wnt bind to Fz is phosphorylation of the Dishevelled (Dsh) protein (Pleasure, 2001).

Figure 1. Summary of canonical and non-canonical Wnt signaling pathway.

Wnt proteins used different signaling pathways

Canonical Wnt/?-catenin signaling pathway

The Wnt signaling activates the canonical pathways by transduction through Fz receptors and LPR5/LPR6 co-receptor to the multifunctional ?-catenin/Tcf dependent pathway (Katoh, 2007). Lack of Wnt signaling activates GSK3? and initiates ?-catenin phosporilation (2008b). The ?-catenin binds to adenomatous polyposis coli (APC) and AXIN which is phosphorilated by casein kinase I? (CKI?) at Ser45 and glycogen sythase kinase 3? (GSK3?) in the NH2 terminal degradation box (2008b; Pleasure, 2001). The phosphorylated ?-catenin is targeted for ?-TRCP1 and ?-TRCP2-mediated ubiquitination and subsequent 26S proteasome degradation which reduce the cytosolic level of ?-catenin (2008b; Pleasure, 2001; Van Scoyk et al., 2008)."

A Wnt-Fz-LRP6 complex formed in the presence of Wnt signaling leads to the phosphorylation of Dishevelled (Dvl) by CKI? and because of its high affinity it binds with FRAT (Yamashina and Kikuchi, 2004). The canonical Wnt signal induces formation of complexes like Dlv/FZD and LRP5/6-AXIN-FRA. Dvl activation leads to phosphorylation and consequently inhibition of GSK3? (Zhang and Yin, 2005). "Inhibition of GSK3? causes the cytosolic nuclear gathering and stabilization of the ?-catenin. The accumulated ?-catenin is translocated to the nucleus, where the ?-catenin forms a complex with members of the transcription factor-T cell factor/lymphoid enhancer factor (TCF/LEF), legless family docking proteins (BCL9 and BCL9L) as well as co-activators such as PYGO family (Frank et al., 2010) and p300 transcription initiator (Katoh, 2007)."The transcription complex TCF/LEF- ?-catenin-Legless-PYGO leads the activation of target genes (Frank et al., 2010)."The activation of target genes of ?-catenin using canonical signaling pathway includes fibroblast growth factor (FGF20), head inducer gene 1 (DKK1), WISP1, VEGFR, the Cox-2, metalloproteinases (MMP2, 3, 7, and 9), cyclin D1, Fra-1, c--Myc, c - Jun, among others (2008b; DasGupta et al., 2005).

The independent non-canonical Wnt signaling pathway

Wnt signaling activates the non-canonical pathways by transduction through Fz receptors and co-receptors such as ROR2 and RYK (2008b; DasGupta et al., 2005). This is apparently independent of the ?-catenin phosphorylation (Liu et al., 2005). Thus, in the lack of canonical signaling pathway, the complex Wnt/jun N-terminal kinase (JNK), polar cell polarity (PCP) and protein kinase C (PKC)/calmodulin kinase II (CAMKII)/nuclear factor of activated T cells (NFAT) calcium dependent (+Ca2), similarly to the canonical signaling pathway, activates the non-canonical signaling pathway by helping to bind Wnt to its receptor Fz (2008b; Katoh, 2007; Pleasure, 2001)."This implicates the activation of small G proteins (GTPases) in the RHOA family like RHOU, RAC and CDC42, as well as downstream protein kinases such as c-Jun NH2 terminal kinase or rho kinase (Shahnazari et al., 2008). The Dvl protein is necessary for signal transduction in canonical and non-canonical signaling (Takahashi-Yanaga and Sasaguri, 2007). However, in the canonical signaling phosphorylation of Dvl is not a prerequisite for its activation (Logan and Nusse, 2004)."

Regulation of Wnt signaling

The Wnt signaling pathways are critical for cell fate and formation during embryogenesis (Katoh, 2007), Wnt signaling is strictly controlled by a large number of extracellular secreted proteins such as DKKs, FRPs, WIF, Cer, and intracellular proteins (Logan and Nusse, 2004; Pleasure, 2001). Intracellular and extracellular proteins are cytosolic (ICAT and NKD) and nuclear (Sox17). Also, Wnt signaling pathways are controlled by gene inhibitors and cross communication between different Wnt signaling pathways (2008b; Logan and Nusse, 2004). For example, the non-canonical pathway might act as regulators of canonical signaling, which often influence the phosphorylation and activation of GSK (Kadoya et al., 2000) . Fz proteins work also as inhibitor during Wnt signaling and transduction through a G-protein (Caruso et al., 2006). Furthermore, Fz activates the Ca2+ signaling pathway with TAK, and Nemo like kinase (NLK) and ends the phosphorylation of the transcription complex (Kuhl et al., 2000).

The ?-Catenin a functional protein during Wnt signaling

The most important protein during Wnt signaling is the ?-catenin (Katoh, 2007). The ?-catenin is a multifunctional molecule, which interacts with other proteins such as cadherins to create cell adhesion by forming a link with the cytoskeleton (2008b; DasGupta et al., 2005). The ?-catenin/cadherins interaction is controled by phosphorylation (Logan and Nusse, 2004). Plakoglobulin, a protein closely related to ?-catenin, which is able to replace ?-catenin functions and acts in the absence of ?-catenin to transmit signals (Katoh, 2007).

The signal transduction of Wnt/?-catenin

Wnt family signaling is regulated by the stability of cytoplasmic ?-catenin protein (Katoh, 2007). This acts as a transcriptional activator of the signaling pathway."In the lack of Wnt signaling a cytoplasmic complex is formed by different proteins, which promote phosphorylation of the ?-catenin (2008b; DasGupta et al., 2005). The ?-catenin phosphorylation allows the catalyzation of inhibitory genes to proteasoma degradation (Liu et al., 2005)."On the nucleus, the expression of target genes is repressed by the family of TCF/LEF1 transcription factors (Maiese et al., 2008)."When the Wnt ligand binds to the complex Fz / LRP, the signal is translated by the cytoplasmic protein intercellular Dissheveled. An unknown mechanism blocks the activity of cytoplasmic degradation."Once the cytoplamic degradation stop his function, the ?-catenin is accumulated and translocated into the nucleus, where TCF/LEF1 interacts with the ?-catenin and activates expression of target genes (Pleasure, 2001).

Shh signal transduction

The Shh signaling pathway shares many features with the Wnt signaling pathway (Varnat et al., 2010)."The regulation of the transcriptional activator CI /GLI is critical for proper Wnt signaling.In the absence of Shh, Ci/Gli complex is partially degraded, but leaves the N-terminal fragment of the protein intact (Katoh, 2007)."The degraded complex is translocated into the nucleus, where it recruits various transcriptional co-repressors and blocks Shh target gene."The Ci/Gli degradation is initiated by phosphorylation of the cytoplasmic proteins through a complex that contains anchor proteins and kinases such as cos2 and Gsk3b (2008a; Katoh, 2007)."The Shh signaling binds with Ptc to release Smoothened (Smo). The Smo is accumulated in the cell surface and interacts with cos2 (Pleasure, 2001)."This interaction causes inhibition of the Ci/Gli degradation and then the non-processed protein is translocated to the nucleus where it activates the expression of target genes (2008b; Logan and Nusse, 2004).

Role of canonical Wnt and Shh on the neural tube morphogenesis

The Wnt and Shh molecules act on neighboring cells as short-range signals (Pleasure, 2001; Zhang and Yin, 2005). They also act like a morphogenes (Pleasure, 2001; Takai et al., 2010). These morphogenes induce different responses in cells located far from signaling production site, depending on their concentration."In addition, several processes are simultaneously regulated by Wnt and Shh signaling proteins (Liu et al., 2003)."In vertebrates, Shh and canonical signaling pathways converge to control the cell specification and proliferation during development of the spinal cord (Lluis et al., 2010; Zhang and Yin, 2005)."In addition, Wnt1 and Wnt3a receptors are necessary for neural tube formation."There is sufficient evidence to assume that Wnt and Shh signals are essential for the regulation and the proliferation of neural precursors and thus neural tube development (Pleasure, 2001)."At the molecular level seems that both signaling pathways are capable to regulate the expression of certain modulators, which are required for cell cycle transition (Zhang and Yin, 2005).

The Wnt controls dorsoventral during embryonic formation

Several Wnt proteins are linked to the formation of the dorsoventral tube axis,i.e., theWnt1 and Wnt3a function during dorsoventral axis formation via the canonical pathway (Tamura et al., 2010). Wnt acts as a dorsal signal to control the expression of markers of neural progenitors (Lustig and Behrens, 2003)."Thus, overexpression of Wnt ligands in the neural tube causes the expression of dorsal proteins such as Pax6 and Pax7 at the expense of ventral markers such as Olig2 and Nkx2.2 (Pleasure, 2001)."Furthermore, the loss of Wnt signaling pathway during tube formation results in a strong ventralization of the neural tube (DasGupta et al., 2005; Pleasure, 2001).Therefore, the Wnt signaling canonical pathway is important for dorsoventral patterning of the neural tube.

The role of Wnt signaling during disease formation and embryo development

Wnt signaling and bone regeneration

A series of studies at the Medical School of Stanford University showed that Wnt proteins can effectively help to regenerate bone (Einhorn, 2010). Previous studies indicated that Wnt protein was useful for bone recovery, however, it was difficult to use as a medical tool because of its chemical properties. Through experiments on mice, researchers discovered that Wnt proteins activate bone stem cells that participate in bone regeneration. In experiments with genetically engineered mice, researchers accelerated bone healing process by applying the modified Wnt protein (Koesters and von Knebel Doeberitz, 2003).

The Wnt made stem cells placed at the site of injury induce division and accelerate maturation to form bone mass more rapidly than in normal mice (Einhorn, 2010). Subsequently, scientists developed a substance called liposomal Wnt3a that produced the same effects in mice without genetic modification (Shahnazari et al., 2008). By injecting liposomal Wnt3a into a bone wound the healing process was accelerated (Einhorn, 2010). It also stimulates bone stem cells formation, increment cell division and promotes cell maturation at the injury site (Zhang et al., 2009). The report indicates that the precise location of the site where the protein must act on stem cells is important for its function (Einhorn, 2010). Without control it can have serious side effects such as excessive formation of bone tissue (Katoh, 2007).

The Wnt signaling in skeletal growth process and embryo development

Wnt proteins have significant function in the process of skeletal growth (Einhorn, 2010; Shahnazari et al., 2008). To prove this hypothesis, researchers made small capsules (liposomes) to deliver the Wnt protein directly into an injury site. After a few days, Wnt protein caused bone restoration and growth (Katoh, 2007). One of the key points of Wnt signaling pathway is the regulation and stability of cytoplasmic protein beta-catenin. Beta-catenin works and function like a transcriptional co-activator (Shahnazari et al., 2008). In the absence of Wnt signal, the cytoplasmic complex is formed by different anchoring proteins such as Axin or APC and kinases like GSK3beta or Cklalfa, which promote the phosphorylation of beta-catenin which can easily be degraded by the proteasome (Tamura et al., 2010).

Tissue and organ development in embryos is controlled by various signaling pathways, which interact to provide information and induce cell development and differentiation. One of the main signaling systems is the Wnt protein pathway (Aoki and Taketo, 2008; Shahnazari et al., 2008). Wnt proteins oriented and promote differentiation on numerous insect and vertebrate embryo cell types (DasGupta et al., 2005; Kim and Han, 2005). Wnt protein could also be applied to improve tissue regeneration in cases of injuries or heart attacks (Cho et al., 2006). It has been shown that the Wnt pathway is essential for preserving the stem cell compartment in intestinal crypts (Katoh, 2007).

Wnt signaling and tissue formation

The Wnt protein is involved in various tissues such as skin, adipose tissue, hematopoietic tissue, and others (Zeng et al., 2007). Developmental biologists know that a particular type of cell to cell communication is called Wnt signaling pathway/beta-catenin. Wnt proteins regulate cell fate of undeveloped cells, like stem cells, in embryonic stages (Aoki and Taketo, 2008). Through a cascade of signals, cells wait to be transformed by specific instruction to undertake a certain task and work together to form a complete embryo (Wang et al., 2006). Wnt signaling also works as a controller of tissue formation, and tells the cell when to stop, so that growth does not become uncontrolled (Takahashi-Yanaga and Sasaguri, 2007).

Network between Wnt signaling and oncodevelopment pathways

Another signaling pathway found in the Wnt family is activated by a different Wnt protein called Wnt5b (Lu et al., 2004; van Tienen et al., 2009). Wnt5b protein turns off genes which had been activated by Wnt/?-catenin. Therefore, Wnt5b slows cell proliferation and restrain regeneration (Lu et al., 2004). The discovery of Wnt5b inhibitory property is important because the Wnt5b gene inhibits a faster bone wound recovery in mammals, particularly human (Pleasure, 2001). Thus, if scientists find a way to interfere with Wnt5b protein when it is signaling cell fate inhibition, Wnt/?-catenin might be able to promote regeneration. Currently, there are drugs that can regulate Wnt family pathway (Cho et al., 2006). These findings are relevant in human medicine and help to understand human development.

The Wnt activity during carcinogenic

With the lack of Wnt signaling, ?-catenin phosphorylation is regulated by a multiprotein complex. This multiprotein is the adenomatous poliposis coli (ACP) tumor supresor, glycogen synthase kinase (GSK3h), and auxin (Koesters and von Knebel Doeberitz, 2003). Once Wnt bind to Fz, a series of events are followed by the destabilization of the complex (Cho et al., 2006). This complex destabilization induces unphosphorylated ?-catenin to accumulate in the nucleus and translocate where h-catenin can works as a co-factor of T-cell factor/lymphoid enhancing factor (TLC/LEF) (Kolligs et al., 2002).

Research has shown that an inherited autosomal dominant condition generates adenomas in the coleorectum (Albuquerque et al., 2010). Human APC, therefore, is inactive in patients with familial adenomatosis polyposis (FAP). In patients with inherited APC, polyps develop everywhere in the intestinal track as well as thyroids and brain. Even though FAP is a rare cancer disease, 85% of the population with colorectal cancer (CRC) shows signs of FAP; thus, CRCs probably mutate from APCs (Kolligs et al., 2002).

The mutation in APCs causes changing in insertion points, deletions of specific bases, and non-sense mutations, which generates premature stop codons after transcription of genes. Most APCs are deletions in the 1309 codon (AAAAG) (Sun et al., 2010). The vast variability in these mutations is due to nature and position of the germline. Most common human mutations of APC are located at the positions 450 and 1878 which result in a relatively stable truncated protein (Luu et al., 2004). Patients who had shown this mutation present carcerigenous cells in the upper gastrointestinal tract and they present other diseases like osteomas, epidesmoids, and desmoids (Lustig and Behrens, 2003). On the contrary, mutation in the 5Vend of APC results in FAP attenuation, which is characterized by late development of carcerigenic cells and a few polyp formations (Turashvili et al., 2006). Also, mutations on 3Vend of APC shows attenuation of FAP and low levels of truncated proteins. The APC is well known as a tumor suppressor; thus, both alleles are affected by suppression activity (Lustig and Behrens, 2003). But, CRCs even with APC mutations always have APC protein remains. In many cases, one allele had truncated mutation and the other allele had either truncated mutation or loss-of-heterozygozity. In general, mutations in codon 1300 are associated with loss-of-heterozygozity (Pena-Hernandez et al., 2008).

Mutation of the Wnt pathway is not restricted to CRC

Currently, a great number of random tumors have been described with mutations on APC and CTNNB1. For example, intestinal cancer shows a ?-catenin mutation. Human melanoma was the first tumor type resulting from mutations in CTNNB1 and APC (Kikuchi and Yamamoto, 2008). Initial research indicated that lack of Wnt signaling plays an important role in the formation of malignant melanoma (Prasad et al., 2007). Currently, it is well known that wnt signaling produces missense mutations in genes such as CTNNB1 and generates mRNA splicing (DasGupta et al., 2005). Thus, the stabilization of the protein was identified on less than 6 lines and the APC gene was missing in the other 2 lines. Additional data suggest that mutation on CTNNB1 and APC represent less than 5% of all melanomas (Katoh, 2008).

Much research has shown the important role of Wnt signaling during mammary cancer development. The induction of Wnt-1 expression in animals generates mammary cancer and salivary adenocarcinomas (Turashvili et al., 2006). In mice, the expression of Wnt-2 gene initiates the formation of tumors. In humans, breast cancer express high levels of Wnt-2, WNT5A, and WNT7B. Furthermore, the over expression of axin in mice generates mammary carcinoma and lymphoid development (Matsuda et al., 2009). The APC mutation in mice showed a retarded development of mammary carcinoma (Li et al., 2003). Therefore, mice showed the development of benign tumors. Mice that lack of Lef1 do not develop mammary glands, whereas lack of Tcf1 helps to develop intestines and mammary glands (Ozaki et al., 2005; Turashvili et al., 2006). These data support that wnt signaling affects mammary carcinogenesis.

Wnt signaling in the adult lung

Adult lung tissue expresses a wide range of Wnt family as well as Fz receptors."For example, the adult lung expresses Wnt-3, Wnt -4, Wnt -5, Wnt -7b, Wnt -10b and Wnt -11 (Kuhl et al., 2000; Van Scoyk et al., 2008)."Likewise, receptors are used by lung tissue in maintenance, thus, receptors like Fz -3, Fz-6, Fz -7, DVL and Dkk are expressed in adult lung (Van Scoyk et al., 2008)."The adult lung cells have low cell differentiation, thus Wnt signaling is not clearly evident (Tennis et al., 2007). But, if an adult organ depends on stem cells and stem cells are controlled by the ?-catenin and Tcf/Lef signaling; adult lung depends on Wnt signaling pathway (Van Scoyk et al., 2008)."For example, the maintenance of lung structures such as hair follicle and dermis requires Wnt signaling, as well as ?-catenin function.

Wnt in lung carcinoma

Cancer is a major cause of death worldwide (Tennis et al., 2007; Van Scoyk et al., 2008)."Understanding of Wnt canonical and non canonical pathway during carcinogenesis is important to early control of aberrant proliferation of cells (Nakatani et al., 2002). Lung cancer is one of the most proliferative carcinoma in humans, but lung cancer development still remains a mystery. The sporadic mutations in suppressor genes control the aberrant formation of carcinoma cells such as the suppressor adenomatous polyposis coli (APC) and ?-catenin."The APC mutations result in the gathering of the ?-catenin into the cell nucleus (Tennis et al., 2007)."The ?-catenin gathering causes the activation of genes such as cyclin D1 and oncogene proteins (c-myc)."The strength of ?-catenin degradation has a positive effect on the activation of genes. The increased concentration of ?-catenin in the cell nucleus increases the possibility of lung cancer (Li et al., 2005)."Mutations in APC and ?-catenin rarely produce carcinoma cells."It has been demonstrated that loss of Wnt7a function increases the formation of carcinoma cells in the lung (Tennis et al., 2007; Van Scoyk et al., 2008)."Also, high concentrations of Wnt1 and WNT2 generate small carcinoma cells in the lungs (Li et al., 2005)."Conversely, the decrease in the concentration of Wnt7 functions as carcinoma lung suppressor (Matsuda et al., 2009; Van Scoyk et al., 2008)."Wnt7 is involved in canonical signaling inhibits proliferation and induces differentiation through JKN/AP1 dependent signaling pathway.

The role of canonical Wnt signaling during development of carcinoma cells is still controversial."Although Wnt5a acts as a regulator during lung development; it acts as an inhibitor of canonical Wnt signaling."Therefore, there are high levels of Wnt5a during metastasis of sarcomas in the lung (Van Scoyk et al., 2008)."At any stage of tumor formation in the lungs, there is a transformation of epithelial-mesenchymal (EMT) and increases of the ?-catenin."Because mutations in ?-catenin are rare, a possible mechanism of control could be the EMT transformation. The EMT transformation results in the formation of cancer on the lung (Tennis et al., 2007)."Recently, Wnt5a has been described as a regulator of fibroblast growth factor (FGF). The sonic hedgehog (Shh) expression was found in high concentrations in lung metastases similar to Wnt family. The lack of regulation of FGF and Shh during canonical Wnt5a signaling is indirectly regulated the formation of carcinoma cells in the lung."However, an imbalance in the canonical Wnt5a signaling causes a phenotype similar to carcinoma in the lungs (Tennis et al., 2007)."The over-expression of Dvl, which is a regulator of Wnt signalization, causes 75% reduction in carcinoma lung cell formation."On the other hand, the low expression of Dkk3, WIF and FRP induces the formation of carcinoma cells in the lung (Kuhl et al., 2000).

Wnt signaling during lung infection

Currently, there is no concrete evidence that Wnt is involved during infection of pulmonary cells (Van Scoyk et al., 2008). But, through research based on typical of respiratory tract infection, we can understand how Wnt signaling functions during lung infection."The Increment of cytokines levels such as IL1, IL6, IL8, IL15, monocyte chemotaxis prote-nas1 (MCP1), TNF, and adhesion molecules (ICAM-1) are key features of pulmonary infection."The high expression of ICAM in the epithelium is necessary for adhesion of leukocytes and the expression of IL-8 is critical for the attraction of neutrophils (Tennis et al., 2007; Van Scoyk et al., 2008)."The neutrophils as well as macrophages contribute to the formation of lung lesions."Increased levels of matrix metallo proteinases (MMP) are also a feature of the lungs during lung inflammation and infection of lung tissue (Chen et al., 2008; Tennis et al., 2007)."Several lung cells such as macrophages, neutrophils and parenchymal cells are able to generate MMP cells. Several MMPs have an important role in lung inflammation and infection."The transcription activation of MMPs is initiated by two pro-inflammatory cytokines and the canonical wnt signaling pathway (Van Scoyk et al., 2008). But, it is not well described if cytokines and the canonical wnt signaling pathway function simultaneously or both act in competition (Tennis et al., 2007)."Undoubtedly, the canonical Wnt1 signaling pathway is linked to pro-MMP3 stimulation and transcription which is used either during lung inflammation or lung tissue infection (Li et al., 2005; Tennis et al., 2007)."Therefore, we need to understand the function of Wnt signaling pathways which is important during carcinoma formation in the lungs and tissue infection.

Wnt signaling and rheumatoid arthritis

Studies of rheumatoid arthritis indicate that Wnt5a-Fz5 signaling significantly aid the development and production of pro-inflammatory cytokines (IL6, IL8, IL15) (Lamb et al., 2005)."The over-expression of Wnt5a increases the production of pro-inflammatory cytokines."In contrast, anti-Wnt5a and anti-Fz-5 antibody reduced cytokine production."In addition, the Wnt5a is to regulate the Shh amount in the lung, but also Wnt5a functions during the formation of arthritis (Rabelo Fde et al., 2010). The over expression of Shh signaling regulates inflammatory process of lungs and intestinal fibrosis (Lamb et al., 2005). Researchers have suggested that Wnt5a acts during the formation of rheumatoid arthritis. It will be necessary to clarify the type of signaling pathway which Wnt uses during the rheumatoid arthritis formation.

The interaction of Wnt signaling with FGF, TGF ? / BMP / Smad pathways

A detailed analysis of the Wnt interactions with other signaling pathways is important to clarify their interactions with other signaling pathways during cell fate and cell proliferation."The Wnt signaling interacts with other signaling pathways to control and regulate cell development and tissue infection of lung disease (Katoh, 2007)."For example, the non-canonical pathway activator Wnt5a has been implicated in the regulation of other several signaling pathways (Liu et al., 2005)."The absence of Wnt5a signaling in animals or knockout genes increases the expression of FGF10 and BMP4 signaling pathways (Pleasure, 2001). This interaction indicates that the Wnt5a non-canonical pathway plays an important role in the regulation of both pathways."FGF10 stimulates cellular proliferation and branching as well as carcinoma lung formation and it also induces delayed expression of late distal epithelial (BMP4) expression (Van Scoyk et al., 2008). Finally, wnt5a expression inhibits lung bud formation and regulation of cell proliferation in the lung.

Studies showed that Wnt family functions as a modulator of signals generates by other signaling pathways (Liu et al., 2005)."For example, the canonical Wnt pathway is an inhibitor of ICCAT, and it also regulates the expression of inhibitory signaling pathway such as BMP and BAMBI. The ICAT works by blocking TCF and p300-s binding sites by binding the ?-catenin domain. The inhibition of ?-catenin dependent on gene transcription, this indicates that BAMBI is controlled by BMP and the canonical Wnt signaling (2008b). The TGF ? and BMP pathways require the function of Smad-s for signal transduction as well as the modulation of ?-catenin."The main role of Smad is activating the TGF-?1 system during lung fibro genesis."Similarly, TGF ?1 functions as an EMT regulator during alveolar epithelial cells transition (Boonchai et al., 2000)."The TGF ? and ?-catenin signaling induces EMT and interacts with the Wnt/TGF."The FGF signaling pathway, Shh, TGF ? and BMP act during tissue repair, fibrosis, and carcinoma formation and metastasis."Therefore, Wnt signaling modulates carcinoma cell formation. Also, Wnt signaling has a direct function in the activation of gene transcription, modulation and regulation of several other signaling pathways during cell fate and cellular proliferation.

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