Received: 22 October 2021 | Revised: 10 February 2022 | Accepted: 7 March 2022

DOI: 10.1002/cbin.11797

Cell Biology
REVIEW International

Wnt signaling pathway: A comprehensive review

Rabia Hayat1 | Maleeha Manzoor2 | Ali Hussain3

1
Institute of Evolution and Marine
Biodiversity, Ocean University of China,
Qingdao, China
2
Department of Zoology, Government College
University, Faisalabad, Pakistan
3
Department of Wildlife and Ecology,
University of Veterinary and Animal Sciences,
Lahore, Pakistan
Correspondence
Maleeha Manzoor, Department of Zoology,
Government College University, Faisalabad,
Pakistan.
Email: maleehamanzoor@gcuf.edu.pk
Abstract
Wnt signaling is an evolutionary cell‐to‐cell coordination mechanism and it is highly
critical for a variety of physiological processes of an organism's body, including stem
cell regeneration, proliferation, division, migration, polarity of a cell, determining fate
of the cell and specification of neural crest, neural symmetry and morphogenesis.
Wnts are extracellular secreted glycol proteins, consisted of a family of 19 human
proteins that represent the complex nature of the regulatory structure and
physiological efficiency of signaling. Moreover, a Wnt/β‐catenin‐dependent path-
way and the β‐catenin‐independent pathway that is further classified into the Planar
Cell Polarity and Wnt/Ca2+ pathways have been established as key signaling nodes
downstream of the frizzled (Fz/Fzd) receptor, and these nodes are extensively
analyzed at biochemical and molecular levels. Genetic and epigenetic activities that
ultimately characterize the pathway and its subsequent responses contribute to
Wnt‐β‐catenin signaling pathway hypo or hyper‐activation and is associated with
the variety of human disorders progression most significantly cancers. Recognizing
how this mechanism operates is crucial to the advancement of cancer prevention
therapies or regenerative medicine methods.

KEYWORDS
cancer, Wnt proteins, Wnt signaling, Wnt/Ca2+, Wnt/β‐catenin‐dependent

1 | INTRODUCTION multiple fields, that is, evolutionary biologists to cellular biologists as

Extensive research work has been dedicated to analyze the signaling
pathways and molecular processes that regulate an organism's
growth in the new era of molecular medicine. In the current research,
this focus is profoundly intertwined and leads to the idea that
identifying the processes that govern natural development will raise
our expectations enormously to deter and manage the pleiotropic
disorders that appear when such pathways go faulty. The Wnt
signaling is among the key pathways about which much work has
been put into delineating (Zhan et al., 2017). An image of a signaling
cascade that is entirely crucial for the developmental process of all
complex organisms along with the development and repair of
different tissue types has been drawn over 40 years of scientific
investigations in various model organisms. While our knowledge of
this complex pathway is indeed very limited, without such initial
efforts, we might not be here as we are currently. Researchers from
well as from embryologists to challenging biochemists, have
contributed important knicks and knacks to crack the biological
puzzles of Wnt signaling. And if we developed deeper insights about
Wnt proteins biological functions, we can more effectively identify
and understand the abnormal signaling which ultimately help us to
recognize its role in the etiology of several diseases like structural and
metabolic disturbances to various types of tumors (Nusse &
Clevers, 2017, Wiese et al., 2018). The title Wnt has been derived
by combining designations of wingless (Wg) polarity gene of
Drosophila segment and homolog of vertebrate, integrated or int‐1
(Holstein, 2012; Logan & Nusse, 2004; Wodarz & Nusse, 1998). From
an evolutionary point of view, Wnt signaling is highly conserved and
contributes significantly to embryogenesis, homeostasis and regen-
eration of adult tissues (Nusse & Clevers, 2017). It is also crucial for
maintaining genetic stability as well as play major role in determining
fate of the cell, differentiation, apoptosis and motility of cells along

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with stem cell maintenance (Clevers, 2006). A variety of disorders,
namely embryonic deformities, degenerative diseases, diabetes,
cancers, and autoimmune diseases are linked with abnormal regula-
tion of Wnt signaling (Clevers & Nusse, 2012; Kahn, 2014; Kumar
et al., 2016; Zhan et al., 2017).
Wnt signaling is categorized into two pathways. One is the
β‐catenin dependent pathway that is also regarded as the canonical
or Wnt/β‐catenin dependent pathway, whereas the second pathway
is the β‐catenin‐independent signaling that is also called as non‐
canonical pathway. This non‐canonical pathway has two classes
+2
including Wnt/planar cell polarity (PCP) and Wnt/calcium (Wnt/Ca )
pathway, which can antagonize Wnt/β‐catenin dependent signaling
in certain cases (Grumolato et al., 2010). The Wnt/β‐catenin
dependent signaling primarily involves in regulation of cell prolifera-
tion, while polarity and mobility of the cell are regulated by
Wnt/β‐catenin independent pathway. (Amin & Vincan, 2012;
Gajos‐Michniewicz & Czyz, 2020; Komiya & Habas, 2008).
Wnts are secretory proteins which are integral for the cell‐to‐cell
communication. Many intracellular signal transduction cascades are
activated by the extracellular Wnt signal, the Wnt/β‐catenin‐
signaling and β‐catenin‐independent signaling (Baarsma & These proteins interact with more than 15 types of cell membrane
Konigshoff, 2017; Habas & Dawid, 2005). Wnt genes expressed
and translated into Wnts. Wnt proteins are cysteine‐rich glycopro-
teins. Secretion of these proteins by cells into the extracellular matrix
of near surroundings cause receptor‐mediated cell signaling (Niehrs &
Acebron, 2012). This protein family consists of approximately 19
secreted cysteine‐rich glycoproteins. These Wnts are of 350–400
amino acids in length. These Wnt proteins are conserved in different
species ranging across invertebrates to mammals (Cadigan &
Nusse, 1997; Pai et al., 2017). Binding of Wnt and Fz family receptor
involves the cysteine‐rich extracellular N‐terminal domain of Fz. This
domain is a member of such receptor family which is coupled with
G‐protein (Pai et al., 2017). Additionally, co‐receptors for modulating
Wnt signaling are also necessary for the interface of Wnt and Fz. For
example, the low‐density lipoprotein‐related protein5/6 (LRP5/6) is
needed for the regulation of the canonical Wnt signaling (Catalano
et al., 2020; Komiya & Habas, 2008).
With the involvement of a broad variety of secretory Wnt
antagonists, one primary layer of Wnt signaling regulation exists in
the extracellular environment. The signal is directed toward
phosphoprotein Disheveled (Dsh/Dvl) in the cytoplasmic matrix after
coupling of Wnt and receptor complex as documented previously
that Dsh could communicate in a direct way with Fz (Dejana, 2010;
Wallingford & Habas, 2005). The Wnt signal splits into at least three
distinct steps at the point of Dsh, including canonical, PCP, and Wnt/
Ca2+ cascades. Dsh is considered a significant downstream part of
this process of transduction and is the 1st cytoplasmic protein to be
pivotally active in all three main Wnt signaling cascades. It is still
uncertain, although, how the regulation and channeling of the signal
into these pathways are controlled by Dsh protein (Catalano
et al., 2020; Komiya & Habas, 2008).
In rats, humans, zebrafish, Xenopus laevis and D. melanogaster
Wnt proteins are found to be conserved across species (Nusse, 2005).
HAYAT ET AL.
Various inhibitors, such as the secreted Fz associated proteins (SFRP)
1‐4 family and Wnt inhibitor factor (WIF) that serve like dissolvable
scavanger of Wnt ligands, also strictly control the Wnt signaling
pathways (Fan et al., 2017). Other molecules adhere to LRP 5/6,
including the Dickkopf (DKK) group constituents and sclerostin, and
intervene with the downstream activation passage of Wnt. This
results in blocking their potential to communicate with Wnt‐Fz
(Nusse & Varmus, 2012, Voronkov & Krauss, 2013). It is believed that
dysregulation of Wnt canonical pathway leads to tumor progression,
chronic inflammation and neurodegenerative disorders, thus natural
antagonists are now being studied for health applications (Cui
et al., 2017).
2 | C O M PO NE N TS O F W NT S I GN A L I N G
The Wnt signaling type components are diverse and comprise a
broad group of secreted proteins for activation of signaling
cascades (evolutionary conserved). 19 Wnt proteins are docu-
mented so far in vertebrates as ligands (Langton et al., 2016).
receptors and co‐receptors, namely Fz, LRP5/6 coreceptor (Janda
et al., 2017; Teratani et al., 2018) and RYK receptor tyrosine kinase
and Ror1 and Ror2 (Receptor tyrosine kinase‐like orphan receptors
1 and 2) (Foulquier et al., 2018). Among them it took more than a
decade to describe Fz as Wnt protein expression receptors.
Additionally, numerous downstream signaling mechanisms are
triggered by other potential receptors and their co‐receptors such
as single transmembrane receptor tyrosine kinase, PTK7 (protein
tyrosine kinase 7), and GPCRs (G‐protein coupled receptor), and so
forth (Farin et al., 2016). Furthermore, interrelated intracellular
intermediaries and many types of endogenous blockers including
DKK and sFRP are also present. Different components of Wnt
signaling are Wnt ligands, Alternative ligands, Extracellular
modulators, Fzd receptors, LRP receptors, Alternative receptors,
Signaling intermediates, β‐catenin destruction complex, Cellular
trafficking and distribution, Effector, Transcription factors and
Intracellular modulators.
3 | MECHANISM
3.1 | Transcription and translocation
Wnt signaling starts by coupling Wnt protein to Fz family receptor's
N‐terminal domain. Wnt proteins are preliminary activation sources
of the signaling pathway. Such receptors subsequently spread across
the plasma membrane seven times and form a separate family of
GPCRs (Bryja et al., 2007). The contact of Wnt protein with the Fz
receptor, co‐receptors are crucial for Wnt signaling activation. The
lipoprotein (LRP)‐5/6. RTK and ROR2 are some examples of such
receptors. A signal is sent toward the phosphoprotein Dsh/Dvl in the
cytoplasm when the receptor is activated.
HAYAT ET AL.
The direct connection of Fz and Dsh helps to carry this signal. In
almost all species, Dsh proteins have been identified and all have the
highly conserved protein domains including a DIX amino‐terminal
domain, a core PDZ region and a DEP carboxy‐terminal region. Such
distinct realms are crucial as this Wnt signal is capable of going out
into several paths after Dsh, and each route interfaces with a distinct
variety of the three domains (Habas & Dawid, 2005).
3.2 | Extracellular regulators
The 19 human Wnt proteins are very promiscuous and each is
capable of binding with more than one of the ten members of the Fz
family, compatible with comparatively high sustainability values of
the binding interfaces. Norrin ligand can also have function for
activating the Wnt/β‐catenin path via coupling with the Wnt
receptors, however, Norrin‐Fz is specialized to make signaling
complex (Komiya & Habas, 2008). Norrin protein in sequence
analysis reveals no associations with the Wnts. For overexpression
and purification, Norrin also faces major challenges as Wnt.
Expression analysis in Escherichia coli and identification of the crystal
structure of Norrin showed fusion with the maltose‐binding protein
C‐terminus have reportedly been uncovered and studied. This
complex shows a dimer made of two interconnected monomers
(Chang et al., 2015; Clevers, 2004). This dimmer locked together
through three intermolecular disulfide bridges. The structural
similarity of Norrin was predicted to match with the cysteine‐knot
cytokines, as well as the crystal structure indicated that it comprises
this basic configuration. Nonetheless, it is totally surprising and
unusual such arrangement of these three intermolecular disulfide
bonds. In Wnts proteins' C‐terminal domain, the detection of the
cytokine‐type fold shows a previously unknown structural resem-
blance of Wnt and Norrin. The additional structural similarities
resulting from future investigations of the alignment of the signaling
complexes Fz and LRP5/6 including these two distinctive ligands are
deemed very fascinating (Shen et al., 2015).
3.3 | Heterodimeric structure of Wnt receptors
Wnt proteins adhere to the complex of the heterodimeric receptor,
containing an Fz as well as an LRP5/6 receptor protein when
interfering with target cells. Seven‐transmembrane receptors are the
10 Fz proteins of mammals having broad extracellular N‐terminal
cysteine‐rich regions (Bhanot et al., 1996), which offer a principal site
for Wnt adhesion (Dann et al., 2001). Multiple binding interfaces are
seen in the configuration of the CRD as it adheres to the Wnt, one of
which includes a hydrophobic furrow that attach to the Wnt molecule
of lipid (Niehrs & Acebron, 2012). The relationship between Wnt‐Fz
is chaste as a solitary Wnt can attach to several Fz proteins (Bhanot
et al., 1996) and vise‐versa, that too confirmed through Wnt‐CRD
complex form (Niehrs & Acebron, 2012). Fzs communicate with an
LRP5 family's single‐pass transmembrane molecule recognized in
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invertebrates as LRP5 and ‐6 and in Drosophila as Arrow (Wehrli
et al., 2000). In a study, two monoclonal antibodies that can work in
opposition to LRP6 along surprising potential by disrupting signaling
via certain Wnt proteins and increase signaling through others were
identified. Such results indicate that Lrp6 have distinct binding
positions for various types of Wnt proteins, since these antibodies
couple with nonoverlapping domains of LRP6 proteins (He
et al., 2004).
Signaling via dimeric Wnt receptors, much like most signal
transduction mechanisms, entails a ligand‐persuaded structural
alteration in receptors accompanied by phosphorylation of main
selected proteins. The bonding of Axin to the LRP6 cytoplasmic tail is
a necessary stage in signaling. Axin‐LRP6 coupling is controlled by at
least two distinct kinases including GSK3 and CK1γ, via LPR6 tail
phosphorylation. In a variety of Wnt signaling elements, namely
β‐catenin, Axin, APC, and possibly LRPs, serine is phosphorylated by
GSK3 in the PPPSP motif of these Wnt components. In membrane,
CK1γ is stabilized via its palmitoylated C terminal and play its role in
phosphorylation of these proteins on sites next to the motif of PPPSP
(Davidson et al., 2005). Whether or how Wnt stimulates these
protein kinases is not evident, while introducing Wnt protein to cells
causes phosphorylation due to CK1γ in mins, indicating an immediate
signal reaction.
4 | EXTRACELLULAR D ISTRIBUTIO N AND
MOVEM ENT
As best shown by Wg, Wnt proteins can act as morphogens intended to
interact both with short and long signaling. The concern of its
distribution and dissemination across the soluble extracellular environ-
ment is raised due to Wg lipidation. Even so, purified Wnt3a through
artificial liposomal packaging shows enhanced activity (Morrell
et al., 2008). Two separate Wg secretory routes have been hypothe-
sized, though not entirely corroborated, for short and long‐distance
signaling. To conceal lipid alterations within (Katanaev et al., 2008), or
attach to lipoprotein molecules, Wg can form multimers that might be
implicated in long‐distance Wg signaling (Panakova et al., 2005). Wg
secretion for long‐distance is directly promoted by the reggie‐1/flotillin‐
2 (membrane microdomain protein) (Katanaev et al., 2008). In the
concentration of Wg morphogen, Wg receptors and heparan sulfate
proteoglycans including Dally and Dally‐like proteins show significant
functions via the modulation of destruction, diffusion, endo/trans‐
cytosis of Wg, and can act as important co‐receptors of low affinity in
Wg signaling (Glinka et al., 2011).
5 | WNT: A DEVELOPMENTAL SIGNALING
PAT HWA Y
The Wnt signaling is specifically categorized into two groups based
on the participation of the β‐catenin a key intracellular molecule. The
canonical Wnt pathway and the Noncanonical Wnt pathway are
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additionally classified as the PCP and Wnt/Ca2+ pathways. The
canonical Wnt signaling is thoroughly studied and described the
signaling cascade, which depends on β‐catenin stabilization leading to
transcriptional activation (Rao & Kuhl, 2010). In specific, most
research is focusing on the pathway for Wnt/β‐catenin, the well‐
known and defined arbitrator in the regulation of proliferation and
migration of cell (Wray & Hartmann, 2012).
The amounts of β‐catenin molecules are lower in a normal
condition lacking Wnt ligand (Figure 1a), but cytoplasmic catenin
interacts with the nominal “destruction complex.” Structural protein,
Axin, adenomatous polyposis coli (APC) of tumor suppressor, STK
(serine/threonine kinases), GSK‐3, CK1 (casein kinase 1, protein
phosphatase 2A, and β‐TrCP (β‐transducing repeat‐containing E3
ubiquitin‐protein ligase) are constituted of this destruction complex
(Stamos & Weis, 2013). When ligation of Wnt ligands with the cell
surface receptors occurred, CK1 and GSK‐3 progressively phospho-
rylate β‐catenin at serine/threonine residues positioned at the
N‐terminal protein region. Then, sequentially this phosphorylated
β‐catenin undergoes ubiquitination for its degradation via E3
ubiquitin ligase β‐TrCP (Azzolin et al., 2014; Stamos & Weis, 2013).
As transcriptional repressors that suppress transcription of the gene,
transcription factor T‐cell factor (TCF) and Groucho generate a
constitutive repressor complex when β‐catenin do not degrade.
Decreased levels of nuclear β‐catenin could trigger and control
transcription of the target gene (Nusse & Clevers, 2017).
The cytoplasmic component of FZD could attach to DVL in the
existence of Wnt ligands (Figure 1b), which will then offer a site for
the destruction of β‐catenin (Gammons & Bienz, 2018). The
suppression of β‐catenin breakdown results once the complex is
employed, where phosphorylation of LRP5/6 via CK‐1 alpha occurs

F I G U R E 1 Canonical pathway signaling Wnt. (a) Signaling via complex of the Fz receptor and LRP5/6 coreceptor in the presence of Wnt
stimulation causes concurrent CK1 and GSK3‐β mediated LRP6 phosphorylation, allowing the diffusion of an Axin‐containing protein complex
toward the plasma membrane from the cytosol. Dvl is attracted to the membrane as well and couples to Fz while with phosphorylated LRP5/6
Axin binds. This complex established at Fz/LRP5/6 of the membrane stimulates β‐cat stabilization by either sequestration and/or Axin
deprivation. In terms of regulating the transcriptional activation of target genes, β‐catenin diffuses into the nucleus where it combines with Lef/
Tcf family subunits to form a composite. (b) The activity of the destruction complex consisting of CKI alpha, GSK3β, APC, Axin in the lack of Wnt
ligand produces a hyperphosphorylated β‐catenin, which is a subject for ubiquitination and proteasome degradation. β‐catenin is destroyed
following phosphorylation and ubiquitination via proteosome. Dvl offers a medium to degrade β‐catenin for selection. The TCF/Groucho
constitutive repressor complex represses the Wnt target genes
HAYAT ET AL.
and allowing LRP5/6 to interact with the destruction complex (Niehrs
& Shen, 2010). Accumulation of β‐catenin in cytoplasm matrix makes
its diffusion to the nucleus. Within the nucleus, it triggers cellular
responses via TCF and/or lymphoid enhancer factor through
controlling its target gene expression. These factors are the activators
of the Wnt pathways (Lee et al., 2014).
Other signaling channels are activated by non‐canonical Wnt
proteins (e.g., Wnt4, Wnt5a, and Wnt11), which can also control
either transcriptional or non‐transcriptional actions in cells. The non‐
canonical route involves the PCP, also recognized as the signaling
pathway for Wnt/c‐Jun N‐terminal kinase (JNK) and the signaling
pathway for Wnt/Ca2+, receptor‐like tyrosine kinase. Wnt/PCP
(shown in Figure 2) ligands namely Wnt5a, Wnt7, and Wnt11 attach
to the FZD receptor. Activation of small GTPases (Rho and Rac
family), and JNK mediated by DVL exert the downstream effectors
that guide cytoskeletal structure and direct cell polarization within
the epithelial sheet plane via regulation of the target gene
transcription. The small GTPase Rac and Rho collectively activate
kinases like Rho and JNK that contribute to downstream (Yang &
Mlodzik, 2015) c‐Jun N‐terminal kinase expression and transcription
factor 2 activation (Sokol, 2015).
The Wnt/Ca2+ pathway (Figure 3), which produces Ca2+ through
G‐proteins, is just another non‐canonical signaling pathway (Nusse &
Clevers, 2017). The Wnt/Ca2+ signaling pathway regulates phospho-
lipase C (PLC) activation, calcium responsive calmodulin kinase II
(CAMK II) and protein kinase C (PKC) enzymes activation, as well as it
F I G U R E 2 Wnt is translocated by Fz
independent of LRP5/6 in the non‐canonical
Wnt/PCP signaling pathway, leads to Dsh
activation. Dsh modulates the Rho activation
via Daam1, which then causes Rho kinase
(ROCK) activation. Via the actin‐binding
protein Profilin, Daam1 also regulates the
polymerization of actin. Rac activation is also
mediated by Dsh, which triggers JNK in
response. For cytoskeletal alterations during
gastrulation, Rock, JNK, and Profilin activation
are combined for Polarization and
translocation of the cell
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also regulates the transcription of activated T‐cell dependent nuclear
factor. Increasing evidence is pointing to the signaling pathway of
Wnt/PCP as a crucial facilitator in the regulation of kidney and renal
disease development (Matsuyama et al., 2014). This pathway in
nephrogenesis is implicated in EMT (Burn et al., 2011). Moreover, a
variety of non‐canonical Wnt ligands that have been conventionally
described can adversely impact the signaling pathway of canonical
Wnt/β‐catenin.
6 | OTHER WNT SI GNALI NG P ATHWAYS
It has been shown that the microtubule cytoskeleton, during neuronal
migration and synapse formation, is regulated by Wnt signaling and
this process relies on GSK3 and Dsh action (Salinas, 2007). One more
Wnt channel by utilizing the Ryk receptor and proto‐oncoprotein Src
governs the neurons repulsion during axonal coordination (Surmann‐
Schmitt et al., 2012). The Rap1‐GTPase that leads to cytoskeletal
regulation is inhibited by Wnt signaling through casein kinase during
gastrulation (Semenov et al., 2007). Wnt signaling through Dsh and
GSK3 negatively controls the TSC2 tumor suppressor for cell growth
to control mechanistic target of rapamycin (Inoki, 2006). For
epithelial polarization and cell mobility, cell polarity and the
microtubule cytoskeleton are modulated by Wnt signaling through
Dsh, aPKC, Par3, Par6, and LGl (Dollar et al., 2005). Wnt signaling
by PKA as well as the transcription factor CREB activates
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muscle‐specific gene expression of MyoD and Myf5 during myogen-
esis (Chen et al., 2005). Wnt signaling through the use of the ROR2
receptor ultimately activates proto‐cadherin PAPC expression
through the CDC42 and JNK channels in gastrulation (Schambony
& Wedlich, 2007). These new pathways lead to complexity of Wnt
signaling which may affect a variety of cellular processes, and
research to explain how these pathways are interconnected remains
crucial.
7 | I N D U C E D CE L L RE S P O N S E S
7.1 | Role of Wnt in embryonic development
Wnt pathways are crucial for the embryonic development and stem
cell proliferation (Kerekes et al., 2021). Multiple signaling pathways
regulate the processes of Neural Crust (NC) induction and specifica-
tion, while Wnt/β‐catenin signaling has a continual role in activating
and maintaining the gene regulatory network during NC induction
and pigment cell specification (Sutton et al., 2021). Components of
Wnt family exhibit expression at the initial stage of embryonic
growth. One of several conserved communication networks that
dictate embryo development is the Wnt/β‐catenin signaling
(Sanz‐Ezquerro et al., 2017; Tepekoy et al., 2015). It contains Wnt
ligands that are produced by cells generating Wnt and that function
HAYAT ET AL.
F I G U R E E 3 Non‐canonical Wnt/Ca2+
signaling pathway. Wnt signaling via Fz
facilitates Dsh activation via G‐protein
activation. Phosphodiesterase PDE suppresses
the PKG and in consequence suppress the
emancipate of Ca2+, is triggered by
Disheveled. By PLC Dsh activates IP3, leading
to the emancipation of intracellular Ca2+,
which regulates CamK11 and calcineurin in
response. To control the fates of a ventral cell,
NF‐AT is stimulated by calcineurin. TAK and
NLK activation occur due to CamK11, which
impedes the activity of β‐catenin/TCF in
controlling the formation of the dorsal axis
negatively. During gastrulation activation of
CDC42 by PKC and DAG occur to initiate
tissue differentiation and cell movements
to affect adjacent Wnt responsive cells across different sites. In
several species, Wnt/β‐catenin signaling is useful in identifying
the dorso‐ventral and anteroposterior body axes (Genikhovich &
Technau, 2017; Niehrs, 2010). Wnt3a and Wnt4 have been reported
to expressed in mice at the stage of 8‐cells (Lloyd et al., 2003).
Expression of Fz5 has been observed in the distal visceral endoderm
(dVE) and later in the anterior visceral endoderm (aVE) at the stage of
peri‐gastrula. While Fz10 was observed to be expressed in the
delamination of the primitive streak of the epiblast. Additionally, it
has been indicated that expression of Fz7 was observed in the
extraembryonic area of pre‐gastrula and the epiblast of 6–7 days
post‐coitum (dpc) embryos, being more anteriorly bound at 7.5 dpc
(Kemp et al., 2007). The signaling by Wnt had also been associated
with parameters controlling the differentiation of the germ layer in
the growing embryo. This was shown by the signaling pathway of
Wnt/β‐catenin that mediated the expression of SRY HMG‐box 17
transcription factor (Sox17) for visceral endoderm patterning as well
as definite endoderm development. Wnt ligand‐dependent β‐catenin
pathway then stimulates a relatively distinctive transcriptional
cascade at the initiation of gastrulation that regulates differentiation
of the anteroposterior axis. In this case, the pathway of
Wnt/β‐catenin is blocked anteriorly, resulting in the head structure
formation, and subsequently activated posteriorly to form tail
structure (Green et al., 2015). The spatial and temporal
Wnt/β‐catenin transcriptional activities regulation is central to
HAYAT ET AL.
such patterning cases by the intervention of secretory antagonists,
epigenetic regulation, activities of various Tcf/Lef factors and the
fusion of signaling with other pathways of development process.
Wnt/β‐catenin signaling also have major role in the morphogenesis
of several tissues originating from the three germ layers, apart from
its early functions in forming the body axes of embryo (Steinhart &
Angers, 2018).
7.2 | Role of Wnt in cell fate specification
Wnt signaling regulates cell fate decisions in diverse contexts during
development, and loss of Wnt signaling in the cranial mesenchyme
results in a robust and binary cell fate switch from cranial bone to
ectopic cartilage. Genetic interaction between the Wnt and ERK
signaling pathways to repress Sox9 and ERK signaling is activated
downstream of Wnt signaling during calvarial osteoblast fate
decisions in vivo (Ibarra et al., 2021)
In a study, 57 genes in 4 functionally linked and enriched classes
were identified in 239 Wnt regulated pathways (Huang et al., 2009).
Groups included are cuticle structural components, transcriptional
factors, signal proteins, and protein kinases. In the lateral hypodermal
cells and the development, 13 out of 57 genes (about 24%) are
expressed (Bruders et al., 2013). The major group of enriched genes, the
cuticle, contains such encoding parts of the outer surface of the worm,
which is synthesized by hypodermal cells. A study identified a group of
cuticular collagen genes whose expression is usually observed in the
mid‐L4 stage in the larva. But in the case of ectopic Wnt signaling these
genes showed expression earlier. Reduced activity for these genes
induced a deficiency in the structure of the adult cuticle. Finding of this
study is in accordance with previous study and supports the theory of
unrecognized function of Wnt signaling in adult cuticle synthesis
(Jackson et al., 2014; Van Camp et al., 2014).
7.3 | Role of Wnt in cell proliferation
To control the proliferation and differentiation of cells, Wnt/β‐
catenin signaling pathway act as a central dogma (Kahn, 2014). This
mechanism is regulated by canonical signaling of Wnt, which tends to
increase β‐catenin in the nucleus and cytoplasm. Transcriptional
regulation of a variety of proteins including cyclin D1 and c‐myc,
which regulate the transition from G1 to S phase of the cell cycle, can
indeed be triggered by elevated β‐catenin. DNA replication and
mitosis triggered by S‐phase initiation. These events are essentially
necessary for the proliferation of the cells (Kaldis & Pagano, 2009).
This controlled spike in proliferation is closely associated with cell
differentiation, so they also divide as the stem cells proliferate.
Throughout embryonic development, it promotes the overall growth
and development of complex tissue structures. This is evident in
mechanisms including the circulatory system where Wnt3a con-
tributes to the hematopoietic stem cells proliferation and propagation
needed for the production of red blood cells (Rasmussen et al., 2018).
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The Wnt/β‐catenin dependent pathway is implicated in the
regulation of both normal and cancer cell proliferation (Holland
et al., 2013; Teo & Kahn, 2010; Valkenburg et al., 2011). Cancer stem
cell biochemistry is distinct from that of most tumor cells. To facilitate
their unregulated expansion, longevity, and proliferation, these so‐called
Wnt‐addicted cells derail and rely on consistent Wnt pathway
regulation. In cancer, via mutations in the sequence of downstream
oncogenes and tumor suppressor genes, Wnt signaling could work
independently without the involvement of typical triggers, it becomes
chronically activated even if a signal is not received by the regular
receptor. In addition, the binding of the β‐catenin to transcription
factors like the TCF4 enzyme causes the required gene activation by the
molecules. This binding is highly inhibited by LF3 in in vitro experiments,
in cell lines, and decreased tumor growth in mice models. It stopped the
replication process and also decrease their ability to spread, all without
disturbing normal cells (Willert & Jones, 2006).
7.4 | Role of Wnt in cell migration
During the development process of an embryo, cell migration
facilitates the body axis establishment, the development of tissues,
the initiation of limbs, and many other processes. Wnt signaling,
especially at the stage of convergence and extension, supports to
instigate these processes. During gastrulation, for appropriate
convergence and extension, mediation from PCP along with the
canonical Wnt pathway is necessary. The Wnt/Ca2+ signaling, which
inhibits convergence and extension when triggered, additionally
controls convergence and extension. In subsequent developmental
stages, Wnt signaling also promotes cell migration by the regulation
of the migration activity of neuroblasts, neural crest cells, tracheal
cells, and myocytes (Schambony & Wedlich, 2013). For example,
myogenesis was found to be caused by Wnt‐1 and Wnt‐3 in chicken
and by Wg in Drosophila melanogaster. Wnts perform an additional
function in regulating the motility of myocytes, in contrast to
determining the action. In the rat, Wnt‐5A and Wnt‐3A triggered in
cardiac myocytes the N‐cadherin expression and fibroblasts expres-
sion of E‐cadherin and M‐cadherin. In the presence of fibroblasts,
increased cell adhesion mediated by cadherin appears to be a
requirement for the myocyte aggregates formation. Wnt‐5A/Wnt‐3A
triggers then reduce the mobility of rat's cardiac myocytes and
facilitate their accumulation. The regulation of myocyte migration by
DWnt‐2 in the male reproductive tract was seen in Drosophila
melanogaster (Von Maltzahn et al., 2012). Non‐canonical Wnt
signaling playing role in regeneration of the intestinal epithelium,
and identify enteroendocrine cell‐released ligands as critical coordi-
nators of intestinal stem cell migration (D. J. K. Hu, Yun, et al., 2021).
7.5 | Role of Wnt in bone formation
Mutations which cause the loss in function in LRP5, a coreceptor of
Wnt, contributed to decreased bone mass in humans, indicated the
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potential contribution of Wnt signaling in regulating bone formation.
Several results obtained from comprehensive studies on mouse and
animal models with Wnt signaling agent mutations have established
that Wnt signaling has possible effects in both normal and
pathophysiological cases of bone formation (Gong et al., 2001; Kato
et al., 2002; Mani et al., 2007). The Wnts serve for cells of osteoblast
precursor and foster their division via the β‐canonical pathway into
mature osteoblasts. In contrast, by monitoring the ratio of the
receptor activator of NF‐kB ligand (RANKL)/osteoprotegerin (OPG)
by a similar mechanism in mature osteoblasts, Wnts inhibit bone loss.
In comparison, scientific investigations have revealed that the non‐
canonical β‐catenin‐independent signaling pathway activation im-
proves the development of osteoclasts in mice macrophage cultures
activated by RANKL (Glass et al., 2005; Maeda, 2007; Spencer
et al., 2006). These findings show that in many facets of bone
development and bone resorption, Wnt‐mediated signaling is
activated.
8 | CLINICAL IMPLICATIONS
Dysregulation of Wnt signal transduction can contribute to the
progression of human diseases, despite the valuable and varying
physiological processes of Wnt signaling. Therefore, these kinds of
diseases, Wnt signaling pathway could also serve as an effective
biomarker, and targeting this pathway is a beneficial option for
therapeutic purposes. Present methods of targeting the Wnt signaling
therefore, mainly concentrated on interventions against cancer.
Conversely, it is possible that abnormal Wnt signaling can be
explored as a therapeutic target for other disorders, like neuro-
degenerative disorders, chronic degenerative bone diseases, and
cardiovascular problems, with the advancement of our understanding
of such pathways.
8.1 | Role of Wnt in cancer
Wnt signaling is among the main development and halting cascades
and is closely allied with cancer. Its role in oncogenesis has been
more notably characterized for colorectal cancer, although in many
other cancer domains, abnormal Wnt signaling is also greatly involved
(Zhan et al., 2017). Many morphological and epigenetic experiments
have attempted to classify new elements of the Wnt pathway and
their roles in recent years. It became clear with the advancement of
sequencing technologies and the detailed structural analysis of
cancer genomes that Wnt pathway mutations have shown frequent
association with cancer progression in humans (Dahmen et al., 2001).
The Wnt signaling action in the field of cancer biology is strikingly
nuanced and continues just slightly grasped because key constituents
of the pathway are already known (Segditsas & Tomlinson, 2006). In
cancer progression and development, a profound information of non‐
canonical Wnt signaling has contributed to revolutionary treatment
interventions. To either trigger or suppress Wnt5a dependent
HAYAT ET AL.
signaling, two Wnt5a analog small peptides, Foxy‐5, and Box‐5,
were already produced, thus mitigating tumor growth in selective
tumors. The first findings of the Foxy‐5 phase I clinical study show
strong therapeutic efficacy (Andersson et al., 2015).
The advent of both Wnt5a agonists and antagonists, the
characterization of responsive tumor subgroups for anti‐secretion
treatment, additionally direct medical trials in the context of tailored
approaches. Though, as evidence of selective medical studies shows,
the risk of significant site‐specific adverse impacts around stem cell
niche areas in the body tends to be addressed in tailor studies and
research on drug safety assessments (Zhan et al., 2017). As Wnt
signaling has crucial roles in carcinogenesis, metastasis, cancer
recurrence, and chemotherapy resistance. Based on these facts,
Wnt represents an appealing therapeutic target for cancer treatment
(Fatima et al., 2021). Any change in Wnt signaling pathway can cause
following types of cancer:
8.1.1 | Pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is currently the third
leading cause of cancer mortality in the United States (Siegel
et al., 2021). WNT ligand signaling plays key roles in PDAC initiation,
progression, dissemination, and therapeutic resistance. Therapeutic
interest is a genetically defined subset of PDAC known to have
increased WNT/β‐catenin transcriptional activity, growth depen-
dency on WNT ligand signaling, and response to pharmacologic
inhibitors of the WNT pathway (Aguilera & Dawson, 2021).
8.1.2 | Lung cancer (LC)
LC occupies the first place in global cancer incidence and death rate.
Development of lungs cancer is closely related to the Wnt/β‐catenin
signaling pathway, and its key molecules, such as Wnt1, β‐catenin,
cyclin D1, and SOX‐2, are expressed to varying degrees in the lung
cancer tissue. Development of novel inhibitors that selectively and
precisely target the Wnt/β‐catenin signaling pathway is still a
promising strategy to generate unique LC treatment options that
will benefit LC patients (Zhu et al., 2021).
8.1.3 | Breast cancer
Wnt/β‐catenin signaling pathway along with other components such
as Axin2, APC, casein kinase Iα, GSK‐3β, protein phosphatase 2A,
FZD7, LRP5, and LRP6 involved in breast cancer metastasis and
progression because of its transcriptional control on epithelial to
mesenchymal transition. Newer approaches using natural, microbial
and chemical agents targeting the Wnt pathway show promising
results to treat breast cancer. Targeted therapy involving drug
combinations is studied in the preclinical and clinical‐stage to
increase effectiveness against breast cancer (Raut et al., 2022)
HAYAT ET AL.
8.1.4 | Ovarian cancer
Ovarian cancer is one of the most common gynecologic malignancies
in women and has a poor prognosis (Shu et al., 2022). Understanding
the mechanisms of ovarian cancer progression and metastasis is
critically important for developing novel therapies (Tian et al., 2022).
HOXB8 promotes cell proliferation, migration and invasion through
modulating Wnt/β‐catenin and STAT3 signaling pathways in ovarian
cancer, suggesting that HOXB8 may provide a promising target for
the therapy of ovarian cancer (Liu et al., 2022).
8.2 | Role of Wnt in type 2 diabetes
Type 2 diabetes mellitus is among the utmost predominant ailments
that induce decreased insulin release and enhanced peripheral insulin
resistance, associated with increased glucose levels or hyperglycemia,
and maybe lethal if left unchecked. As Wnt signaling contributes to
insulin levels, it is believed that the defective pathway is responsible
for diabetes progression. For example, Wnt5b overexpression can
enhance the susceptibility because of its function in adipocyte
differentiation, since obesity and type 2 diabetes are co‐morbid
(Welters et al., 2008). Wnt signaling is a powerful mitochondrial
biogenesis modulator that inevitably causes an increase in the
development of DNA and cellular damage found to increase reactive
oxygen species (ROS). This disruption caused by ROS is important
since it is known to induce immediate resistance to hepatic insulin, or
insulin resistance caused by damage. Genetic changes in transcription
factors linked with Wnt signaling like TCF7L2 are associated with
enhanced sensitivity (Schinner, 2009). A Chinese herbal medicine
(TSF) helps in the treatment of diabetic kidney disease. This may
alleviate myocardial fibrosis in KKAy mouse models by inhibiting
TGF‐β/Smad and Wnt/β‐catenin signaling pathways. These findings
may increase our knowledge regarding effect of TSF in diabetes
(L. Hu, Wang, et al., 2021).
8.3 | Role of Wnt in neuronal disorder
Enhanced Wnt1 expression can contribute to synaptic reorganization
and plasticity in schizophrenia patients' brains. The propensity to
schizophrenia is linked with many SNPs in Fz3, and GSK3 behavior in
schizophrenia appears to be changed reportedly (Katsu et al., 2003).
Mutated β‐catenin signaling can be implied in the progression of the
most prevalent neurological disorder, Alzheimer's disease (AD),
identified by extracellular deposits of amyloid β‐peptide, intracellular
hyperphosphorylated tau accumulation, and specific cholinergic
neuronal loss (Luo et al., 2007). The constituents of presenilin
complexes are β‐Catenin and GSK3β, and the lack of Wnt/β‐catenin
activity could be underlying the unset and AD progression (Luo
et al., 2007; Mudher & Lovestone, 2002,). AD is a brain‐related
disorder linked with aging, with synaptic loss and dementia (Selkoe &
Hardy, 2016). Wnt/β‐catenin signaling in the brain is not only
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required for the survival of neurons and neurogenesis but also plays a
vital role in controlling synaptic plasticity and the stability and
functionality of the blood‐brain barrier (Nusse & Clevers, 2017).
Besides, Wnt/β‐catenin signaling activity reduces the generation of
amyloid‐β and hyperphosphorylation of tau protein in the brain.
Wnt/β‐catenin signaling is substantially inhibited by many pathogenic
pathways in the AD brain. Therefore, a remarkable potential for
the rational design of innovative AD strategies is to restore
Wnt/β‐catenin signaling (Jia et al., 2019). Parkinson's disease (PD)
is the most common disorder of movement (Giovannini et al., 2021).
The level of Wnt/β‐catenin signaling activation could explain the high
phenotypical heterogeneity of autism spectrum disorders and be
instrumental in the development of new diagnostics tools and
therapies (Caracci et al., 2021).
8.4 | Role of Wnt in rheumatoid arthritis (RA)
RA is the deadliest autoimmune disease and is controlled by many
factors like genetic makeup, environmental constituents, and
dysfunctional signaling pathways. RA usually results in inflammation
and severe deformities in joints of the various parts of the body (Salt
& Crofford, 2012). One of the signaling pathway that is playing a vital
role in controlling RA is the WNT signaling path. But there are not
enough clear experimental proofs that will explain the complete
involvement of this pathway in RA (Miao et al., 2013, 2015).
Many clinical studies have been held on a various number of RA
patients and all these studies enlighten the involvement of one of
genes of Wnt gene family which is Wnt7b. The expression of these
genes is upregulated in such patients. These studies also show the
elevated level of production of some inflammatory proteins and
agents like TNF‐α, IL‐1β, and IL6 in RA synovium. An interesting point
rise after these studies is that these inflammatory agent's TNF‐α,
IL‐1β, and IL6 are produced in a massive amount in normal synovial
cells which were transfected by the Wnt7b genes. This shows a
linkage between the inflammatory mediators and Wnt genes. These
elevated levels of inflammation proteins also scale up the expression
level of Wnt/Fz.
A comparative study conducted between RA patient and other
patients who do not have much difference in the number of various
proteins like the Wnt inducible signaling pathway proteins (WISP),
ligands, and Fz receptors were observed between them. Unlike the
patients who don't have RA, the RA patients have higher level of
these proteins in their body (Cheon et al., 2004; Nakamura
et al., 2005).
Upregulation and downregulation of different pathways and
factors collectively result in RA and osteoarthritis like the degradation
of the matrix that is found in cartilaginous joints due to the
switching on of Wnt/β‐catenin signaling in chondrocytes, whereas
the erosion of bones and their remodeling into a completely different
morphology occur due to switching off Wnt signals. The correct
expression of different proteins like fibronectin and metalloprotei-
nase which are involved in bone formation is controlled by the Wnt
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signaling pathway (Schett et al., 2008; Shi et al., 2016). Functionally,
a slight divergence in the expression of Wnt signals results in the
advancement of cell proliferation and differentiation (Cheon et al., 2004).
Different in vitro studies have been carried out on the fibroblast‐like
synoviocytes (FLS) of RS patients. These FLS show a gradual and
consistent higher expression level of Wnt5a and Fz5. These studies
show a direct relation between FLS, Wnt5a and Fz5. The activation of
these pathways also activates the FLS in RA patients. These activation
events are not influenced by the inflammatory environment around
them (Cheon et al., 2004, Shi et al., 2016). Thus for the treatment of
refractory synovitis, all the receptors that are antagonistic to Fz5 can be
considered effective (Sen et al., 2001). Td‐FLS, fd‐FLS, and fibrocytes
from patients with RA expressed similar levels of Wnt5a and a set of
Wnt5a receptors/coreceptors. Wnt5a stimulated the expression of the
pro‐inflammatory targets, and in conjunction with SFRP5 inhibited the
gene expression of TCF4 and the protein levels of the canonical
coreceptor LRP5 (Mahmoud et al., 2021). Knockdown of phospholipase
D1 (PLD1) could reduce RA‐FLSs metastasis as well as inflammatory
response by modulating the activity of NF‐κB and Wnt/β‐catenin
pathways (Zhang et al., 2021).
8.5 | Wnt signaling in systemic sclerosis (SSc)
SSc is a lethal autoimmune disease with highest mortality rate. The
main cause of this deadly disease is the hyperactivation of the
immune system along with the severe damage to the vascular
muscles and the agglomeration of various excretory proteins in skin
and organs (Antic et al., 2013). The Wnt pathway is clearly elevated in
SSc and is pro‐fibrotic via activation of canonical Wnt signaling
(Henderson et al., 2021). The regulatory mechanics of various
signaling machinery play a part in the activation of this disease.
Many events like the upregulated expression of Wnt signaling
components Wnt1, Wnt10b, Fzd2, nuclear β‐catenin, and LEF‐1
notices in the patients of this disease, these relations directly pointed
toward skin fibrosis (Leah, 2013; Svegliati et al., 2014). Many in vivo
studies in mice show two major events one is the activation of
fibroblast‐specific dominant active β‐catenin and the other is the de‐
active form of fibroblast‐specific dominant de‐active β‐catenin which
are involved in the fibrosis. Mice with fibroblast‐specific dominant
active β‐catenin show abrupt thickening and collagen accumulation in
the skin and within two weeks they develop fibrosis and result in the
differentiation of fibroblasts into myofibroblasts. In contrast, the
deactivation of fibroblast‐specific β‐catenin reduced the bleomycin‐
induced fibrosis (Beyer et al., 2012). In addition, another in vitro study
indicates the involvement of the Wnt3a in the induction of β‐catenin
for the stimulation of fibroblast proliferation, contraction of collagen
gel, and differentiation of myofibroblast, and increased expression of
profibrotic genes. In contrast, Wnt3a has a repressing power over
adipogenesis but has accelerated effects on the myofibroblast
differentiation in subcutaneous preadipocytes (Antic et al., 2013).
Another study determined the effect of icaritin has an anti‐skin
fibrotic effect through activation of AMPK signaling and inhibition of
HAYAT ET AL.
WNT/β‐catenin signaling. Results indicated the potential role of IT in
the treatment of scleroderma and provide novel insight for the
selection of drug therapy for scleroderma (Li et al., 2021). All these
studies indicate that these Wnt pathways are playing a lead role in
tissue fibrosis. Keeping in view, researchers put forward many
different approaches that target these pathways and help in the
treatment of SSc. These approaches including tankyrase inhibitors,
porcupine inhibitors, and antagonists of cofactor recruitment to
β‐catenin have prominent effects in animal treatment models
(Distler et al., 2013; Konigshoff et al., 2009).
8.6 | Wnt signaling in inflammatory bowel
disease (IBD)
IBD is a disorder in which the body's immune response acts against
the natural microflora of the intestine. These microflorae have
positive impacts on digestion. This results in the inflamed colon and
small intestine. To date, an involvement of Wnt signaling in IBD
pathogenesis has been broadly recognized (Shi et al., 2016). Some
previous studies indicate the hyperactive response of the Wnt
signaling pathway along with a cascade of other interlinked signaling
factors Wnt2, Wnt5a, Wnt5b, Fzd2, Fzd4, Fzd6, LRP6, Dvl, DKK1,
and SFRP1 in both ulcerative colitis (UC) and Crohn disease (CD)
tissues (Hughes et al., 2011; Tuller et al., 2013). In human UC
different microarray analysis of various Wnt pathway genes have
been carried out which indicates the upregulated expression of
Wnt2b, Wnt3a, Wnt5b, Wnt6, Wnt7, Wnt9, Wnt11, Fzd3, Fzd4,
DKK4, and Dvl2 and downregulated mechanics of Fz1 and Fz5 in
comparison to non‐IBD (You et al., 2008). Another analytical
technique known as IHC staining is also performed for the
confirmation which also enlightens that in human UC tissues the
expression of β‐catenin and Wnt associated cancer genes E‐cadherin,
cyclin D1, and c‐myc expressions was unregulated (Van Dekken
et al., 2007). Recently a new genome profiling study reported that in
IBD patients there are visible signs of activation of Wnt signals that
are part of the epithelial lining of the intestine and a visible
suppression in the non‐canonical Wnt signaling pathways. Along
with this another important point also reveals that the process of
mesenchymal cells has an antagonistic effect as it induces the non‐
canonical signals and cause the suppression of canonical Wnt
signaling cascade. This results in lowering and decreased inflamma-
tion levels in and IBD positive rats (Xing et al., 2015).
8.7 | Role of Wnt in cardiovascular diseases
Cardiogenesis and heart diseases both are regulated and controlled
by canonical and non‐canonical Wnt signaling pathways (Olson &
Schneider, 2003; Van Gijn et al., 2002). For instance, an in vivo
disease carried out on mice as a model organism indicates that if the
mice lack Dvl1 are transfected by myocardial infarction have more
chances of infract rupture. Neovascularization in the infarct area is
HAYAT ET AL.
also being affected by the Wnt signaling. Proper cardiac function,
accuracy and maintenance of optimal infarct size are also achieved by
the overexpression of sFRP1 (Barandon et al., 2003). Rats used as a
study model for cardiac hypertrophy shows upregulation of Fz2 (Van
Gijn et al., 2002). If the Wnt pathway got disrupted or dysfunctional
due to any reason, it results in cardiovascular inflammation,
decreasing plasticity of cells, abnormal levels or accumulation of
cholesterol, and abnormal metabolic response to injuries and trauma.
Another important cofactor of the Wnt signaling pathway known as
LRP6 has a major role in the cardio metabolic‐related diseases
confirmed by human and mice genetical analysis. Different biological
weapons can be used as a therapeutic agents for the targeting of Wnt
signals and controlling all the factors interlinked with this pathway
and result in many deadly and lethal diseases (Gay & Towler, 2017;
Krishna et al., 2017).
9 | C ONC LUS I ON
Wnt signaling is an important pathway crucial for the appropriate
development of cells at the embryonic and mature stage by
maintaining cell to cell communication. Wnt signaling further
subdivided into three pathways each having its usefulness. Several
key components of this dynamic system and their potential role
have also characterized. This review provided a comprehensive
overview of Wnt signaling, its components, mechanisms, its role in
developmental stages, and its importance for clinical implications.
Wnt/β‐catenin dependent signaling pathway is the most studied
pathway. Several studies have described the role of different Wnt
proteins in the progression of several types of cancer, diabetes,
neuronal disorder, IBS, RA, SSc, and cardiovascular diseases. The
study of potential role in these diseases makes the Wnt pathway an
important biomarker for establishing novel therapeutic strategies to
treat and prevent such life threatening diseases.
10 | PER SP ECT IV ES
It has been established that for the proper development and
homeostasis of nearly all tissues, Wnt ligands are important.
Genome, biochemical and functional research have highlighted
several components of Wnt signaling in recent decades and have
uncovered their cellular processes. Major gaps exist, though,
especially concerning the signal transduction pathways mediated
by Wnt proteins and β‐catenin. For instance, while Wnt's
configurations in complex with the Fz CRD offered a description
of the ligand‐receptor binding, it remains an open question that how
this is related to possible allosteric alterations in Fz's heptahelical
clusters to transmit signals to the intracellular matrix components. It
remains poorly described that how Wnts co‐work with Fz and co‐
receptors LRP5/6, and what is the exact structure of the complexes
formed. Another poorly known aspect is the recruitment by active
Fz receptors of Dsh/Dvl proteins, and how this contributes to the
Cell Biology | 11
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inhibition of destructive complex function. Moreover, several new
cancer medications are nonspecifically engineered to suppress Wnt
signaling, indicating they affect both normal and cancer cells, which
may lead to severe negative impacts. A major difficulty lies in
designing a strategy that is sufficiently successful to target the
dysregulated Wnt pathway while restricting danger to the normal
functioning of the Wnt pathway, guaranteeing that its crucial
position remains unchanged in various essential biological pro-
cesses. Help to effectively understand the potential pathogenic
functions in human disorders with abnormal Wnt signaling, but also
to present possibilities for appropriate drug development to target
the pathways.
A UT H O R C O N T R I B U TI O NS
Contributed to manuscript writing: Rabia Hayat. Did critical discus-
sions: Maleeha Manzoor. Helped in revision of the manuscript: Ali
Hussain.
DATA AVAILABILITY STATEMENT
Data sharing not applicable—no new data generated.
ORC I D
Maleeha Manzoor http://orcid.org/0000-0002-0393-6766
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How to cite this article: Hayat, R., Manzoor, M., & Hussain, A.
(2022). Wnt signaling pathway: A comprehensive review. Cell
Biology International, 1–15.
https://doi.org/10.1002/cbin.11797