Wingless Gene Signalling in Lung Cancer

The Wnt signal transduction pathway was named after the wingless gene, the Drosophila homologous gene of the first mammalian Wnt gene characterized, int-1, was discovered by Roeland Nusse and Harol Varmus in 1982. The first Secreted Wnt ligands have been shown to activate signal transduction pathways and trigger changes in gene expression, cell behavior, adhesion, and polarity. In mammalian species, Wnt proteins comprise a family of 19 highly conserved signaling molecules. Wnt signaling has been described in at least three pathways, with the best-understood canon- ical pathway, in which Wnt ligands bind to two distinct families of cell surface receptors, the Frizzled (Fz) receptor family and the LDL receptor-related protein (LRP) family, and activate target genes through stabilization of ß-catenin in the nucleus.

Wnt proteins can also signal by activating calmodulin kinase II and protein kinase C (known as the Wnt/Ca 2+ pathway), which involves an increase in intracellular Ca 2+, or Jun N-terminal kinase (JNK) (known as the planar cell polarity pathway), which controls cytoskeletal rearrangements and cell polarity Wnt proteins are secreted glycoproteins of around 40 kDa, with a large number of conserved cysteine residues. They are produced by different cell types, and in humans 19 Wnt proteins currently have been identified. It was found that cysteine palmitoylation is essential for the function of Wnt proteins, and it is reported that Porcupine (Porc), required in Wnt-secreting cells, shows homology to acyltransferases in the endoplasmic reticulum (ER). Taken together, it appears that Porc may be the enzyme responsible for cys-Wnt Signaling in Stem Cells and Lung teine palmitoylation of the Wnt proteins. In addition, studies in Drosophila revealed that the seven transmembrane proteins Wntless (Wls) and Evenness interrupted (Evi) are essential for Wnt secretion. In the absence of Wls/Evi, primarily residing in the Golgi apparatus, Wnts are retained inside the Wnt-producing cells. Furthermore, extracellular heparan sulfate proteoglycans (HSPGs) may also play a role in the transport or stabilization of Wnt proteins.

 Reception and transduction of Wnt signals involve interaction of Wnt proteins with members of two distinct families of cell surface receptors, the Frizzled (Fz) gene family and the LDL receptor-related protein (LRP) family. Fz proteins bind Wnts through an extracellular N- terminal cysteine-rich domain (CRD), and most Wnt proteins can bind to multiple Fz receptors and vice versa.. Ten human Fz proteins have been identified so far, and their general structure is similar to that of seven-transmembrane G protein-coupled receptors, suggesting that Fz proteins may use heterotrimeric G proteins to transduce Wnt signals. A single-pass transmembrane molecule of the LRP family, identified as LRP5 or 6, is also required for the signaling. It appears that surface expression of both receptor families is required to initiate the Wnt signal, although formation of trimeric complexes involving Wnt molecules with Fz and LRP5/6 has yet to be validated. In addition, two tyrosine kinase receptors, Derailed and Ror2, have been shown to bind Wnts. Derailed binds Wnts through its extracellular WIF (Wnt inhibitory factor) domain, and Ror2 binds Wnts through a Wnt binding CRD motif. Signaling events downstream of these alternative Wnt receptors remain largely unclear.

Secreted inhibitory proteins can sequester Wnt ligands from their receptors. Among these are the secreted Frizzled-related proteins (SFRPs) and the Wnt inhibitory factor-1 (WIF-1). The human SFRP family consists of five members, each containing a CRD domain. The biology of SFRPs is, however, complex, and in some cases, they may act as Wnt agonists. WIF-1 does not have any sequence homology with SFRPs but contains a unique evolutionarily conserved WIF domain and five epidermal growth factor (EGF)-like repeats. A third class of extracellular Wnt inhibitor is represented by the Dickkopf (Dkk) family, which antagonizes Wnt signaling pathway through inactivation of the surface receptors LRP5/6.

When Wnt signaling is in the "off state", cytosolic ß-catenin is phosphorylated by the serine/threonine kinases casein kinase I (CKI) and GSK3ß at four N-terminal residues. The scaffolding proteins Axin and APC mediate the interaction between the kinases and ß-catenin. These proteins form a ß-catenin degradation complex that allows phosphorylated ß-catenin to be recognized by ß-TrCP and subsequently targeted for ubiquitination and proteasome degradation. In the nucleus, the TCF/DNA-binding proteins form a complex with Groucho and act as repressors of Wnt target genes when the Wnt signal is absent.

Groucho can interact with histone deacetylases, which makes the DNA refractive to transcriptional activation. Upon interaction of the Wnt ligands with their receptors, the Fz/LRP coreceptor complex activates the canonical signaling pathway. Fz can physically interact with Dishevelled (Dvl), a cytosolic protein that functions upstream of ß-catenin and the kinase GSK3ß. Then the scaffold protein axin translocates to the membrane, where it interacts with either the intracellular tail of LRP or with Fz bound Dvl. Removing axin from the destruction complex promotes ß-catenin stabilization. The "on" and "off" states of Wnt signaling control phosphorylation status of Dvl protein. It remains unclear, however, whether the binding of Wnt to Fz regulates a direct Fz-Dvl interaction and how phosphorylated Dvl functions during Wnt signal transduction. With the help of BCL9 stabilized ß-catenin enters the nucleus and competes with Groucho for binding to TCF/LEF, recruits Pygopus, and converts the TCF repres-Wnt Signaling in Stem Cells and Lung sor complex into a transcriptional activator complex. A large number of Wnt signaling target genes, including c-Myc, cyclin D1, MMP-7, and WISP, have been identified.

The Wnt signaling pathway plays an important role in cell differentiation and proliferation, and when aberrantly activated, it contributes to most of the features that characterize malignant tumors, including evasion of apoptosis, tissue invasion and metastasis, self-sufficiency of growth signals, insensitivity to growth inhibitors, and sustained angiogenesis.

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Javed Shaik is a Graduate in Biotechnology, and is a enthusiast in Cancer Education and Research. He runs a blog - dedicated to helping persons who face cancer with information on early detection, treatment and education.

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