Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene. [5] [6]
Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene. [5] [6]
The WNT gene family consists of structurally related genes that encode secreted signaling lipid modified glycoproteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. [7] This gene is a member of the WNT gene family. The WNT5A is highly expressed in the dermal papilla of depilated skin. It encodes a protein showing 98%, 98%, and 87% amino acid identity to the mouse, rat and the xenopus Wnt5a protein, respectively. Wnts, specifically Wnt5a, have also been positively correlated and implicated in inflammatory diseases such as rheumatoid arthritis, tuberculosis, and atherosclerosis. A central player and active secretor of Wnt5a in both cancer and these inflammatory diseases are macrophages. [8] [9] Experiments performed in Xenopus laevis embryos have identified that human frizzled-5 (hFz5) is the receptor for the Wnt5a ligand and the Wnt5a/hFz5 signaling mediates axis induction. [6] However, non-canonical Wnt5a has also been shown to bind to Ror1/2, RYK, and RTK depending on cell and receptor context to mediate a variety of functions ranging from cell proliferation, polarity, differentiation and apoptosis. [10] [11]
WNT5A is a signaling molecule expressed embryonically during gastrulation in various developing body regions including the caudal mesoderm of the primitive streak, lateral mesoderm, cranial neural crest cells, midbrain, frontal face region, limb buds, mammary gland mesenchyme, caudal region, genital primordia and tailbud. [12] [13] [14] [15] [16] Wnt5a-knockout mice (Wnt5a-/-) died shortly after birth and displayed a plethora of abnormalities, making loss of Wnt5a lethal. [15] When compared to wild-type (WT) controls, Wnt5a-/- embryos developed shorter primitive streaks. Following primitive streak formation, during body axis patterning, Wnt5a-/- embryos also developed a shortened anterior-posterior (A-P) body axis in which the vertebral column was reduced in size due to smaller vertebrae and the lack of a proportion of caudal vertebrae. The resulting abnormalities found were fusion of vertebrae and ribs, and fusion and absence of thoracic, sacral, and tail vertebrae. Since Wnt5a is strongly expressed in the posterior portion of developing embryos, it is not surprising that the lower body were more greatly affected. The tail especially lacked vertebrae and was significantly shortened. [15] As seen in the vertebral column, the nose, mandible, tongue and limbs were also shortened with loss of Wnt5a in both mice and chicks. [15] [17] Wnt5a is normally expressed at the distal end of limb buds and is involved with outgrowth and patterning of the limbs. [18] [15] [17] With loss of Wnt5a, limb shortening is exaggerated as it continues towards the digits. Similar to the vertebral column, more distal structures were found fused and some absent [15] [17]
The Wnt5a gene is also a key component in posterior development of the female reproductive tract, development of the uterine glands postnatally, and the process of estrogen mediated cellular and molecular responses. [19] Wnt5a is expressed throughout the endometrial stroma of the mammalian female reproductive tracts and is required in the development of the posterior formation of the Müllerian ducts (cervix, vagina). [20] A Wnt5a absence study was performed by Mericskay et al. on mice and showed the anterior Müllerian-derived structures (oviducts and uterine horns) could easily be identified, and the posterior derived structures (cervix and vagina) were absent showing that this gene is a requirement for its development. [19] Other members of the WNT family that are required for the development of the reproductive tract are Wnt4 and Wnt7a. [20] Failure to develop reproductive tract will result in infertility. Not only is the WNT5A gene responsible for this formation but also is significate in the postnatal production of the uterine glands otherwise known as adenogenesis which is essential for adult function. [19] In addition to these two developments Wnt5a it needed for the complete process of estrogen mediated cellular and molecular responses. [19]
Wnt ligands are classically described as acting in an autocrine/paracrine manner. [21] [22] [23] Wnts are also hydrophobic with significant post-translational palmitoylation and glycosylation. [24] [25] These post-translational modifications are important for docking to extracellular lipoprotein particles allowing them to travel systemically. [26] [27] Additionally, due to the high degree of sequence homology between Wnts many are characterized by their downstream actions.
Wnt5a is implicated in many different types of cancers. [28] However, no consistent correlation occurs between cancer aggressiveness and Wnt5a signaling up-regulation or down-regulation. The WNT5A gene has been shown to encode two distinct isoforms, each with unique functions in the context of cancer. [29] The two isoforms are termed Wnt5a-long (Wnt5a-L) and Wnt5a-short (Wnt5a-S) because Wnt5a-L is 18 amino acids longer than Wnt5a-S. [29] These 18 amino acids appear to have contrasting roles in cancer. Specifically, Wnt5a-L inhibits proliferation and Wnt5a-S increases proliferation. [29] This may account for the discrepancies as to the role of Wnt5a in various cancers; however, the significance of these two isoforms is not completely clear. [30] Elevated levels of beta-catenin in both primary and metastases of malignant melanoma have been correlated to improved survival and a decrease in cell markers of proliferation. [31]
Increasing evidence has implicated Wnt5a in chronic inflammatory disorders. [32] In particular Wnt5a has been implicated in atherosclerosis. [33] [34] It has been previously reported that there is an association between Wnt5a mRNA and protein expression and histopathological severity of human atherosclerotic lesions as well as co-expression of Wnt5a and TLR4 in foam cells/macrophages of murine and human atherosclerotic lesions. [35] [36] However, the role of Wnt proteins in the process and development of inflammation in atherosclerosis and other inflammatory conditions is not yet clear.
Some of the benefits of targeting this signaling pathway include: [37]
• Many of the current DNA-targeting anticancer drugs carry the risk of giving rise to secondary tumors or additional primary cancers.
• Preferentially killing rapidly replicating malignant cells via cytotoxic agents cause serious side effects by injuring normal cells, particularly hematopoietic cells, intestinal cells, hair follicle and germ cells.
• Differentiated tumor cells in a state of quiescence are typically not affected by drugs can may account for tumor recurrence.
In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.
Frizzled-2(Fz-2) is a protein that in humans is encoded by the FZD2 gene.
Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.
Frizzled-3(Fz-3) is a protein that in humans is encoded by the FZD3 gene.
Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.
Frizzled-7(Fd-7) is a protein that in humans is encoded by the FZD7 gene.
Frizzled-10(Fz-10) is a protein that in humans is encoded by the FZD10 gene. Fz-10 has also been designated as CD350.
Frizzled-4(Fz-4) is a protein that in humans is encoded by the FZD4 gene. Fz-4 has also been designated as CD344.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.
Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.
Proto-oncogene protein Wnt-3 is a protein that in humans is encoded by the WNT3 gene.
Protein Wnt-5b is a protein that in humans is encoded by the WNT5B gene.
Wingless-type MMTV integration site family, member 2, also known as WNT2, is a human gene.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
The TCF/LEF family is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic and stem-cell development, but also had been found to play a role in cancer and diabetes. TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.