The Wnt signaling pathways are a group of

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

pathways which begin with

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that pass signals into a cell through

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s. The name Wnt is a

portmanteau A portmanteau word, or portmanteau (, ) is a blend of wordsparacrine 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 ove ...

) or same-cell communication (

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...

). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three pathways are activated by the binding of a Wnt-protein

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

to a

Frizzled Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol. Species distribution Fri ...

family

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

, which passes the biological signal to the Dishevelled protein inside the cell. The canonical Wnt pathway leads to regulation of

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

, and is thought to be negatively regulated in part by the

SPATS1 Spermatogenesis associated serine rich 1 (SPATS1) is a protein which in humans is encoded by the SPATS1 gene. It is also known by the aliases Dishevelled-DEP domain interacting protein (DDIP), Spermatogenesis Associated 8 (SPATA8), and serin-rich ...

gene. The noncanonical planar cell polarity pathway regulates the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

that is responsible for the shape of the cell. The noncanonical Wnt/calcium pathway regulates

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

inside the cell. Wnt signaling was first identified for its role in

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

, then for its function in

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

. The embryonic processes it controls include

body axis Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

patterning,

cell fate Within the field of developmental biology, one goal is to understand how a particular cell develops into a final cell type, known as fate determination. Within an embryo, several processes play out at the cellular and tissue level to create an organ ...

specification,

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

and

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...

. These processes are necessary for proper formation of important tissues including bone, heart and muscle. Its role in

was discovered when genetic mutations in Wnt pathway proteins produced abnormal fruit fly

embryos An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sper ...

. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice. Wnt signaling also controls

tissue regeneration In biology, regeneration is the process of renewal, restoration, and tissue growth that makes genomes, cells, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of rege ...

in adult bone marrow, skin and intestine. This pathway's clinical importance was demonstrated by

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

that lead to various diseases, including

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

and

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...

type II diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

and others. In recent years, researchers reported first successful use of Wnt pathway inhibitors in mouse models of disease.

History and etymology

The discovery of Wnt signaling was influenced by research on

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

(cancer-causing)

retroviruses A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase e ...

. In 1982,

Roel Nusse Roeland "Roel" Nusse (born 9 June 1950, Amsterdam) is a professor at Stanford University and an investigator at the Howard Hughes Medical Institute. His research was seminal in the discovery of Wnt signaling, a family of pleiotropic regulators in ...

and Harold Varmus infected mice with mouse mammary tumor virus in order to mutate mouse genes to see which mutated genes could cause breast tumors. They identified a new mouse proto-oncogene that they named int1 (integration 1). Int1 is highly conserved across multiple species, including humans and '' Drosophila''. Its presence in '' D. melanogaster'' led researchers to discover in 1987 that the int1 gene in ''Drosophila'' was actually the already known and characterized ''Drosophila'' gene known as Wingless (Wg). Since previous research by Christiane Nüsslein-Volhard and Eric Wieschaus (which won them the Nobel Prize in Physiology or Medicine in 1995) had already established the function of Wg as a segment polarity gene involved in the formation of the body axis during

, researchers determined that the mammalian int1 discovered in mice is also involved in embryonic development. Continued research led to the discovery of further int1-related genes; however, because those genes were not identified in the same manner as int1, the int gene nomenclature was inadequate. Thus, the int/Wingless family became the Wnt family and int1 became Wnt1. The name Wnt is a

portmanteau A portmanteau word, or portmanteau (, ) is a blend of words

Proteins

Wnt comprises a diverse family of secreted lipid-modified signaling glycoproteins that are 350–400

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

in length. The lipid modification of all Wnts is

palmitoleoylation Palmitoleoylation is type of protein lipidation where the monounsaturated fatty acid palmitoleic acid is covalently attached to serine or threonine residues of proteins. Palmitoleoylation appears to play a significant role in trafficking and ta ...

of a single totally conserved serine residue. Palmitoleoylation is necessary because it is required for Wnt to bind to its carrier protein Wntless (WLS) so it can be transported to the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

for secretion and it allows the Wnt protein to bind its receptor Frizzled Wnt proteins also undergo

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...

, which attaches a carbohydrate in order to ensure proper secretion. In Wnt signaling, these proteins act as

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...

to activate the different Wnt pathways via paracrine and autocrine routes. These proteins are highly conserved across species. They can be found in mice, humans, ''Xenopus'', zebrafish, ''Drosophila'' and many others.

Mechanism

Foundation

Wnt signaling begins when a Wnt protein binds to the N-terminal extra-cellular cysteine-rich domain of a

(Fz) family receptor. These receptors span the

seven times and constitute a distinct family of G-protein coupled receptors (GPCRs). However, to facilitate Wnt signaling, co-receptors may be required alongside the interaction between the Wnt protein and Fz receptor. Examples include lipoprotein receptor-related protein ( LRP)-5/6, receptor tyrosine kinase (RTK), and ROR2. Upon activation of the receptor, a signal is sent to the phosphoprotein Dishevelled (Dsh), which is located in the cytoplasm. This signal is transmitted via a direct interaction between Fz and Dsh. Dsh proteins are present in all organisms and they all share the following highly conserved

protein domains In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

: an amino-terminal DIX domain, a central PDZ domain, and a carboxy-terminal

DEP domain In molecular biology, the DEP domain (Dishevelled, Egl-10 and Pleckstrin domain) is a globular protein domain of about 80 amino acids that is found in over 50 proteins involved in G-protein signalling pathways. It was named after the three protei ...

. These different domains are important because after Dsh, the Wnt signal can branch off into multiple pathways and each pathway interacts with a different combination of the three domains.

Canonical and noncanonical pathways

The three best characterized Wnt signaling pathways are the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between the categories is that a canonical pathway involves the protein beta-catenin (β-catenin) while a noncanonical pathway operates independently of it. Canonical Wnt pathway (height=375px)

Canonical pathway

The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. Without Wnt, β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins: Axin,

adenomatosis polyposis coli Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-c ...

(APC), protein phosphatase 2A (PP2A),

glycogen synthase kinase 3 Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen s ...

(GSK3) and casein kinase 1α (CK1α). It degrades β-catenin by targeting it for ubiquitination, which subsequently sends it to the

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

to be digested. However, as soon as Wnt binds Fz and LRP5/ 6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of the negative Wnt regulator, Axin, and the destruction complex to the plasma membrane.

Phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

by other proteins in the destruction complex subsequently binds Axin to the cytoplasmic tail of LRP5/6. Axin becomes de-phosphorylated and its stability and levels decrease. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF (T-cell factor/lymphoid enhancing factor) transcription factors. β-catenin recruits other transcriptional coactivators, such as

BCL9 B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the ''BCL9'' gene. Function BCL9, together with its paralogue gene BCL9L (BCL9 like or BCL9.2), have been extensively studied for their role as transcriptional beta-cateni ...

Pygopus ''Pygopus'' is a genus belonging to the family of Australian legless lizards (Pygopodidae). Members of this genus are also commonly called scaly-foot. Species Within the genus ''Pygopus'' the following five species are recognized as being valid. ...

and Parafibromin/Hyrax. The complexity of the transcriptional complex assembled by β-catenin is beginning to emerge thanks to new high-throughput

proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...

studies. However, a unified theory of how β‐catenin drives target gene expression is still missing, and tissue-specific players might assist β‐catenin to define its target genes. The extensivity of the β-catenin interacting proteins complicates our understanding: β-catenin may be directly phosphorylated at Ser552 by Akt, which causes its disassociation from cell-cell contacts and accumulation in cytosol, thereafter 14-3-3ζ interacts with β-catenin (pSer552) and enhances its nuclear translocation.

and

have been reported, in fact, to possess several β-catenin-independent functions (therefore, likely, Wnt signaling-independent). Non pcp

Noncanonical pathways

The noncanonical planar cell polarity (PCP) pathway does not involve β-catenin. It does not use LRP-5/6 as its co-receptor and is thought to use NRH1, Ryk,

PTK7 Tyrosine-protein kinase-like 7 also known as colon carcinoma kinase 4 (CCK4) is a receptor tyrosine kinase that in humans is encoded by the ''PTK7'' gene. Function Receptor protein tyrosine kinases transduce extracellular signals across the cel ...

or ROR2. The PCP pathway is activated via the binding of Wnt to Fz and its co-receptor. The receptor then recruits Dsh, which uses its PDZ and DIX domains to form a complex with Dishevelled-associated activator of morphogenesis 1 (

DAAM1 Dishevelled-associated activator of morphogenesis 1 is a protein that in humans is encoded by the ''DAAM1'' gene. Evidence of alternative splicing has been observed for this gene but the full-length nature of these variants has not been determined ...

). Daam1 then activates the small G-protein

Rho Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...

through a guanine exchange factor. Rho activates

Rho-associated kinase Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCKs (R ...

(ROCK), which is one of the major regulators of the

. Dsh also forms a complex with rac1 and mediates

profilin Profilin is an actin-binding protein involved in the dynamic turnover and reconstruction of the actin cytoskeleton. It is found in all eukaryotic organisms. Profilin is important for spatially and temporally controlled growth of actin microfilame ...

binding to actin. Rac1 activates JNK and can also lead to actin polymerization.

Profilin Profilin is an actin-binding protein involved in the dynamic turnover and reconstruction of the actin cytoskeleton. It is found in all eukaryotic organisms. Profilin is important for spatially and temporally controlled growth of actin microfilame ...

binding to actin can result in restructuring of the cytoskeleton and

gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...

Noncanonical Wnt-calcium pathway (height=375px)

The noncanonical Wnt/calcium pathway also does not involve β-catenin. Its role is to help regulate calcium release from the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) in order to control intracellular calcium levels. Like other Wnt pathways, upon ligand binding, the activated Fz receptor directly interacts with Dsh and activates specific Dsh-protein domains. The domains involved in Wnt/calcium signaling are the PDZ and DEP domains. However, unlike other Wnt pathways, the Fz receptor directly interfaces with a trimeric G-protein. This co-stimulation of Dsh and the G-protein can lead to the activation of either PLC or cGMP-specific PDE. If PLC is activated, the plasma membrane component PIP2 is cleaved into DAG and IP3. When IP3 binds its receptor on the ER, calcium is released. Increased concentrations of calcium and DAG can activate Cdc42 through PKC. Cdc42 is an important regulator of ventral patterning. Increased calcium also activates calcineurin and CaMKII. CaMKII induces activation of the transcription factor NFAT, which regulates cell adhesion, migration and tissue separation. Calcineurin activates TAK1 and

NLK Serine/threonine protein kinase NLK is an enzyme that in humans is encoded by the ''NLK'' gene. Its name is an abbreviation for ''Nemo-Like Kinase'', Nemo (nmo) being the ''Drosophila'' ortholog Sequence homology is the biological homology b ...

kinase, which can interfere with TCF/β-Catenin signaling in the canonical Wnt pathway. However, if PDE is activated, calcium release from the ER is inhibited. PDE mediates this through the inhibition of PKG, which subsequently causes the inhibition of calcium release.

Integrated Wnt Pathway

The binary distinction of canonical and non-canonical Wnt signaling pathways has come under scrutiny and an integrated, convergent Wnt pathway has been proposed. Some evidence for this was found for one Wnt ligand (Wnt5A). Evidence for a convergent Wnt signaling pathway that shows integrated activation of Wnt/Ca2+ and Wnt/β-catenin signaling, for multiple Wnt ligands, was described in mammalian cell lines.

Other pathways

Wnt signaling also regulates a number of other signaling pathways that have not been as extensively elucidated. One such pathway includes the interaction between Wnt and GSK3. During cell growth, Wnt can inhibit GSK3 in order to activate mTOR in the absence of β-catenin. However, Wnt can also serve as a negative regulator of mTOR via activation of the tumor suppressor TSC2, which is upregulated via Dsh and GSK3 interaction. During myogenesis, Wnt uses PA and CREB to activate MyoD and Myf5 genes. Wnt also acts in conjunction with Ryk and Src to allow for regulation of neuron repulsion during

axonal guidance Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they man ...

. Wnt regulates

when CK1 serves as an inhibitor of Rap1-ATPase in order to modulate the cytoskeleton during gastrulation. Further regulation of gastrulation is achieved when Wnt uses ROR2 along with the CDC42 and JNK pathway to regulate the expression of PAPC. Dsh can also interact with aPKC,

Pa3 PA3 may refer to: * ALCO PA-3, a diesel locomotive * ''Paranormal Activity 3'', a 2011 American horror film * Pennsylvania Route 3 * Pennsylvania's 3rd congressional district Pennsylvania's third congressional district includes several areas o ...

, Par6 and LGl in order to control cell polarity and

microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

cytoskeleton development. While these pathways overlap with components associated with PCP and Wnt/Calcium signaling, they are considered distinct pathways because they produce different responses.

Regulation

In order to ensure proper functioning, Wnt signaling is constantly regulated at several points along its signaling pathways. For example, Wnt proteins are

palmitoylated Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane protein ...

. The protein ''

porcupine Porcupines are large rodents with coats of sharp spines, or quills, that protect them against predation. The term covers two families of animals: the Old World porcupines of family Hystricidae, and the New World porcupines of family, Erethizont ...

'' mediates this process, which means that it helps regulate when the Wnt ligand is secreted by determining when it is fully formed. Secretion is further controlled with proteins such as GPR177 (wntless) and

evenness interrupted Evenness may refer to: *Species evenness *evenness of numbers, for which see parity (mathematics) ** evenness of zero, a special case of the above See also *Even (disambiguation) Even may refer to: General * Even (given name), a Norwegian male p ...

and complexes such as the retromer complex. Upon

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

, the ligand can be prevented from reaching its receptor through the binding of proteins such as the stabilizers Dally and glypican 3 (GPC3), which inhibit diffusion. In cancer cells, both the heparan sulfate chains and the core protein of GPC3 are involved in regulating Wnt binding and activation for cell proliferation. Wnt recognizes a heparan sulfate structure on GPC3, which contains IdoA2S and GlcNS6S, and the 3-O-sulfation in GlcNS6S3S enhances the binding of Wnt to the heparan sulfate glypican. A cysteine-rich domain at the N-lobe of GPC3 has been identified to form a Wnt-binding hydrophobic groove including phenylalanine-41 that interacts with Wnt. Blocking the Wnt binding domain using a nanobody called HN3 can inhibit Wnt activation. At the Fz receptor, the binding of proteins other than Wnt can antagonize signaling. Specific

antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

include

Dickkopf Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. The most well-studied is DKK1, Dickkopf-related protein 1 (DKK1). DKK proteins inhibit the Wnt signaling pathway coreceptors LRP5 and LRP6. They bind with high affini ...

(Dkk), Wnt inhibitory factor 1 (WIF-1), secreted Frizzled-related proteins (SFRP), Cerberus, Frzb,

Wise WISE may refer to: Arts, entertainment, and media * WISE (AM), a radio station licensed to Asheville, North Carolina *WISE-FM, a radio station licensed to Wise, Virginia * WISE-TV, a television station licensed to Fort Wayne, Indiana Education * ...

SOST Sost or SOST may refer to: Places *Sost, Afghanistan, a village in Badakhshan Province *Sost, Pakistan, the last town inside Pakistan on the Karakoram Highway before the Chinese border * Sost, Hautes-Pyrénées, a commune in France Other uses ...

, and

Naked cuticle Naked cuticle (Nkd) is a conserved family of intracellular proteins encoded in most animal genomes. The original mutants were discovered by 1995 Nobel laureates Christiane Nüsslein-Volhard and Eric F. Wieschaus and colleagues in their genetic sc ...

. These constitute inhibitors of Wnt signaling. However, other molecules also act as activators.

Norrin Norrin, also known as Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein (EVR2) is a protein that in humans is encoded by the ''NDP'' gene. Mutations in the NDP gene are associated with the Norrie disease. Function Signal ...

and R-Spondin2 activate Wnt signaling in the absence of Wnt ligand. Interactions between Wnt signaling pathways also regulate Wnt signaling. As previously mentioned, the Wnt/calcium pathway can inhibit TCF/β-catenin, preventing canonical Wnt pathway signaling.

Prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...

is an essential activator of the canonical Wnt signaling pathway. Interaction of PGE2 with its receptors E2/E4 stabilizes β-catenin through cAMP/PKA mediated phosphorylation. The synthesis of PGE2 is necessary for Wnt signaling mediated processes such as tissue regeneration and control of stem cell population in zebrafish and mouse. Intriguingly, the unstructured regions of several oversized Intrinsically disordered proteins play crucial roles in regulating Wnt signaling.

Induced cell responses

Embryonic development

Wnt signaling plays a critical role in embryonic development. It operates in both vertebrates and invertebrates, including humans, frogs, zebrafish, ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

'', ''Drosophila'' and others. It was first found in the segment polarity of Drosophila, where it helps to establish anterior and posterior polarities. It is implicated in other developmental processes. As its function in ''Drosophila'' suggests, it plays a key role in

formation, particularly the formation of the anteroposterior and

dorsoventral Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

axes. It is involved in the induction of

cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...

to prompt formation of important organs such as lungs and ovaries. Wnt further ensures the development of these tissues through proper regulation of

and migration. Wnt signaling functions can be divided into axis patterning, cell fate specification, cell proliferation and cell migration.

Axis patterning

In early embryo development, the formation of the primary body axes is a crucial step in establishing the organism's overall body plan. The axes include the anteroposterior axis, dorsoventral axis, and right-left axis. Wnt signaling is implicated in the formation of the anteroposterior and dorsoventral (DV) axes. Wnt signaling activity in anterior-posterior development can be seen in mammals, fish and frogs. In mammals, the

primitive streak The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the ...

and other surrounding tissues produce the morphogenic compounds Wnts, BMPs,

FGFs Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...

, Nodal and retinoic acid to establish the posterior region during late gastrula. These proteins form concentration gradients. Areas of highest concentration establish the posterior region while areas of lowest concentration indicate the anterior region. In fish and frogs, β-catenin produced by canonical Wnt signaling causes the formation of organizing centers, which, alongside BMPs, elicit posterior formation. Wnt involvement in DV axis formation can be seen in the activity of the formation of the

Spemann organizer The Spemann-Mangold organizer is a group of cells that are responsible for the induction of the neural tissues during development in amphibian embryos. First described in 1924 by Hans Spemann and Hilde Mangold, the introduction of the organizer prov ...

, which establishes the dorsal region. Canonical Wnt signaling β-catenin production induces the formation of this organizer via the activation of the genes twin and siamois. Similarly, in avian gastrulation, cells of the

Koller's sickle In avian gastrulation, Koller's sickle is a local thickening of cells at the posterior edge of the upper layer of the area pellucida called the epiblast. Koller's sickle is crucial for avian development, due to its critical role in inducing the di ...

express different mesodermal marker genes that allow for the differential movement of cells during the formation of the primitive streak. Wnt signaling activated by FGFs is responsible for this movement. Wnt signaling is also involved in the axis formation of specific body parts and organ systems later in development. In vertebrates,

sonic hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...

(Shh) and Wnt morphogenetic signaling gradients establish the dorsoventral axis of the central nervous system during neural tube axial patterning. High Wnt signaling establishes the dorsal region while high Shh signaling indicates the ventral region. Wnt is involved in the DV formation of the central nervous system through its involvement in

axon guidance Axon guidance (also called axon pathfinding) is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they mana ...

. Wnt proteins guide the axons of the spinal cord in an anterior-posterior direction. Wnt is also involved in the formation of the limb DV axis. Specifically, Wnt7a helps produce the dorsal patterning of the developing limb. In the embryonic differentiation waves model of development Wnt plays a critical role as part a signalling complex in competent cells ready to differentiate. Wnt reacts to the activity of the cytoskeleton, stabilizing the initial change created by a passing wave of contraction or expansion and simultaneously signals the nucleus through the use of its different signalling pathways as to which wave the individual cell has participated in. Wnt activity thereby amplifies mechanical signalling that occurs during development.

Cell fate specification

Cell fate specification or cell differentiation is a process where undifferentiated cells can become a more specialized cell type. Wnt signaling induces differentiation of pluripotent stem cells into

mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...

and

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...

progenitor cells. These progenitor cells further differentiate into cell types such as endothelial, cardiac and vascular smooth muscle lineages. Wnt signaling induces blood formation from stem cells. Specifically, Wnt3 leads to mesoderm committed cells with

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

potential. Wnt1 antagonizes neural differentiation and is a major factor in self-renewal of neural stem cells. This allows for regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation. Wnt signaling is involved in germ cell determination, gut tissue specification,

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...

development, lung tissue development, trunk neural crest cell differentiation, nephron development, ovary development and sex determination. Wnt signaling also antagonizes heart formation, and Wnt inhibition was shown to be a critical inducer of heart tissue during development, and small molecule Wnt inhibitors are routinely used to produce cardiomyocytes from pluripotent stem cells.

Cell proliferation

In order to have the mass differentiation of cells needed to form the specified cell tissues of different organisms, proliferation and growth of embryonic stem cells must take place. This process is mediated through canonical Wnt signaling, which increases nuclear and cytoplasmic β-catenin. Increased β-catenin can initiate transcriptional activation of proteins such as

cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...

and '' c-myc'', which control the G1 to

S phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...

transition in the cell cycle. Entry into the S phase causes DNA replication and ultimately

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

, which are responsible for cell proliferation. This proliferation increase is directly paired with cell differentiation because as the stem cells proliferate, they also differentiate. This allows for overall growth and development of specific tissue systems during embryonic development. This is apparent in systems such as the circulatory system where Wnt3a leads to proliferation and expansion of hematopoietic stem cells needed for red blood cell formation. The biochemistry of

cancer stem cell Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. ...

s is subtly different from that of other tumor cells. These so-called Wnt-addicted cells hijack and depend on constant stimulation of the Wnt pathway to promote their uncontrolled growth, survival and migration. In cancer, Wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. β-catenin binds to transcription factors such as the protein TCF4 and in combination the molecules activate the necessary genes. LF3 strongly inhibits this binding ''in vitro,'' in cell lines and reduced tumor growth in mouse models. It prevented replication and reduced their ability to migrate, all without affecting healthy cells. No cancer stem cells remained after treatment. The discovery was the product of " rational drug design", involving AlphaScreens and ELISA technologies.

Cell migration

Cell migration during embryonic development allows for the establishment of body axes, tissue formation, limb induction and several other processes. Wnt signaling helps mediate this process, particularly during convergent extension. Signaling from both the Wnt PCP pathway and canonical Wnt pathway is required for proper convergent extension during gastrulation. Convergent extension is further regulated by the Wnt/calcium pathway, which blocks convergent extension when activated. Wnt signaling also induces cell migration in later stages of development through the control of the migration behavior of

neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...

s, neural crest cells, myocytes, and tracheal cells. Wnt signaling is involved in another key migration process known as the epithelial-mesenchymal transition (EMT). This process allows epithelial cells to transform into mesenchymal cells so that they are no longer held in place at the laminin. It involves cadherin down-regulation so that cells can detach from laminin and migrate. Wnt signaling is an inducer of EMT, particularly in mammary development.

Insulin sensitivity

Insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

is a peptide hormone involved in glucose homeostasis within certain organisms. Specifically, it leads to upregulation of glucose transporters in the cell membrane in order to increase glucose uptake from the bloodstream. This process is partially mediated by activation of Wnt/β-catenin signaling, which can increase a cell's insulin sensitivity. In particular, Wnt10b is a Wnt protein that increases this sensitivity in skeletal muscle cells.

Clinical implications

Cancer

Since its initial discovery, Wnt signaling has had an association with cancer. When Wnt1 was discovered, it was first identified as a proto- oncogene in a mouse model for breast cancer. The fact that Wnt1 is a homolog of Wg shows that it is involved in embryonic development, which often calls for rapid cell division and migration. Misregulation of these processes can lead to tumor development via excess cell proliferation. Canonical Wnt pathway activity is involved in the development of benign and malignant breast tumors. The role of Wnt pathway in tumor chemoresistance has been also well documented, as well as its role in the maintenance of a distinct subpopulation of cancer-initiating cells. Its presence is revealed by elevated levels of β-catenin in the nucleus and/or cytoplasm, which can be detected with immunohistochemical staining and Western blotting. Increased β-catenin expression is correlated with poor prognosis in breast cancer patients. This accumulation may be due to factors such as mutations in β-catenin, deficiencies in the β-catenin destruction complex, most frequently by mutations in structurally disordered regions of APC, overexpression of Wnt ligands, loss of inhibitors and/or decreased activity of regulatory pathways (such as the Wnt/calcium pathway). Breast tumors can metastasize due to Wnt involvement in EMT. Research looking at metastasis of basal-like breast cancer to the lungs showed that repression of Wnt/β-catenin signaling can prevent EMT, which can inhibit metastasis. Wnt signaling has been implicated in the development of other cancers. Changes in CTNNB1 expression, which is the gene that encodes β-catenin, can be measured in breast,

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, prostate,

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

, and other cancers. Increased expression of Wnt ligand-proteins such as Wnt1, Wnt2 and Wnt7A were observed in the development of

, oesophageal cancer and ovarian cancer respectively. Other proteins that cause multiple cancer types in the absence of proper functioning include ROR1, ROR2,

SFRP4 Secreted frizzled-related protein 4 is a protein that in humans is encoded by the ''SFRP4'' gene. Function Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putati ...

, Wnt5A, WIF1 and those of the TCF/LEF family. Wnt signaling is further implicated in the pathogenesis of bone metastasis from breast and prostate cancer with studies suggesting discrete on and off states. Wnt is down-regulated during the dormancy stage by autocrine Dkk1 to avoid immune surveillance, as well as during the dissemination stages by intracellular Dact1. Meanwhile Wnt is activated during the early outgrowth phase by E-selectin. The link between PGE2 and Wnt suggests that a chronic inflammation-related increase of PGE2 may lead to activation of the Wnt pathway in different tissues, resulting in

Type II diabetes

Diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

is a common disease that causes reduced insulin secretion and increased

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

in the periphery. It results in increased blood glucose levels, or

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

, which can be fatal if untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved. Overexpression of Wnt5b, for instance, may increase susceptibility due to its role in adipogenesis, since obesity and type II diabetes have high comorbidity. Wnt signaling is a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS) known to cause DNA and cellular damage. This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance. Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are linked to increased susceptibility.

References

External links

* {{DEFAULTSORT:Wnt Signaling Pathway Signal transduction Genes Evolutionary developmental biology