Wnt signaling pathway

Source: Wikipedia, the free encyclopedia.

The Wnt signaling pathways are a group of

autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.[2][3]

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

transcription, and is thought to be negatively regulated in part by the SPATS1 gene.[4] The noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell. The noncanonical Wnt/calcium pathway regulates calcium
inside the cell.

Wnt signaling was first identified for its role in

embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice. Wnt signaling also controls tissue regeneration in adult bone marrow, skin and intestine.[5]

This pathway's clinical importance was demonstrated by

type II diabetes and others.[6][7] In recent years, researchers reported first successful use of Wnt pathway inhibitors in mouse models of disease.[8]

History and etymology

The discovery of Wnt signaling was influenced by research on

retroviruses. In 1982, Roel Nusse 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).[3][9]

Int1 is highly conserved across multiple species, including humans and

embryonic development, researchers determined that the mammalian int1 discovered in mice is also involved in embryonic development.[10]

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

portmanteau of int and Wg and stands for "Wingless-related integration site".[3]

Proteins

Crystal structure of Wnt8 bound to the Frizzled8 cysteine rich domain. Wnt resembles a hand that is "pinching" Frizzled with its thumb and forefinger.
Crystal structure of Wnt8 (rainbow coloring) bound to the cysteine rich domain of Frizzled8 (green).

Wnt comprises a diverse family of secreted

ligands to activate the different Wnt pathways via paracrine and autocrine routes.[2][7]

These proteins are highly conserved across species.[3] They can be found in mice, humans, Xenopus, zebrafish, Drosophila and many others.[17]

Species Wnt proteins
Homo sapiens
WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16
Mus musculus
 (Identical proteins as in H. sapiens)		 Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, Wnt10A, Wnt10B, Wnt11, Wnt16
Xenopus Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt11R
Danio rerio
 Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt16
Drosophila Wg, DWnt2, DWnt3/5, DWnt 4, DWnt6, WntD/DWnt8, DWnt10
Hydra hywnt1, hywnt5a, hywnt8, hywnt7, hywnt9/10a, hywnt9/10b, hywnt9/10c, hywnt11, hywnt16
C. elegans mom-2, lin-44, egl-20, cwn-1, cwn-2 [18]

Mechanism

Figure 2. Wnt binds to (activates) the receptor. Axin is removed from the "destruction complex." β-Cat moves into the nucleus, binds to a transcription factor on DNA, and activates transcription of a protein. "P" represents phosphate.
Figure 1. Wnt does not bind to the receptor. Axin, GSK and APC form a "destruction complex," and β-Cat is destroyed.

Foundation

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

protein domains: an amino-terminal DIX domain, a central PDZ domain, and a carboxy-terminal DEP domain. 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.[21]

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.[19]

Canonical Wnt pathway

Canonical pathway

The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of

β-catenin-independent functions (therefore, likely, Wnt signaling-independent).[31][32][33]

Noncanonical PCP pathway

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

JNK and can also lead to actin polymerization. Profilin binding to actin can result in restructuring of the cytoskeleton and gastrulation.[7][34]

Noncanonical Wnt/calcium pathway

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

CaMKII. CaMKII induces activation of the transcription factor NFAT, which regulates cell adhesion, migration and tissue separation.[7] Calcineurin activates TAK1 and NLK kinase, which can interfere with TCF/β-Catenin signaling in the canonical Wnt pathway.[35] 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.[7]

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.[36] Some evidence for this was found for one Wnt ligand (Wnt5A).[37] 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.[38]

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

axonal guidance. Wnt regulates gastrulation 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, Par6 and LGl in order to control cell polarity and microtubule 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.[7]

Regulation

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

GPR177 (wntless) and evenness interrupted and complexes such as the retromer complex.[7][24]

Upon secretion, 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[42][43] and the core protein[44][45] of GPC3 are involved in regulating Wnt binding and activation for cell proliferation.[46][47] 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.[48] 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.[45][49] Blocking the Wnt binding domain using a nanobody called HN3 can inhibit Wnt activation.[45]

At the Fz receptor, the binding of proteins other than Wnt can antagonize signaling. Specific

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.[7][24] Prostaglandin E2 (PGE2) 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.[5] Intriguingly, the unstructured regions of several oversized intrinsically disordered proteins play crucial roles in regulating Wnt signaling.[52]

Induced cell responses

Embryonic development

Wnt signaling plays a critical role in embryonic development. It operates in both

ovaries. Wnt further ensures the development of these tissues through proper regulation of cell proliferation and migration. Wnt signaling functions can be divided into axis patterning, cell fate specification, cell proliferation and cell migration.[53]

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

Spemann organizer, 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.[36][53] Similarly, in avian gastrulation, cells of the Koller's sickle 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.[54][55]

Wnt signaling is also involved in the axis formation of specific body parts and organ systems later in development. In vertebrates,

sonic hedgehog (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.[56] Wnt is involved in the DV formation of the central nervous system through its involvement in axon guidance. Wnt proteins guide the axons of the spinal cord in an anterior-posterior direction.[57] Wnt is also involved in the formation of the limb DV axis. Specifically, Wnt7a helps produce the dorsal patterning of the developing limb.[36][53]

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.[58][59]

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

neural crest cell differentiation, nephron development, ovary development and sex determination.[53] Wnt signaling also antagonizes heart formation, and Wnt inhibition was shown to be a critical inducer of heart tissue during development,[63][64][65] and small molecule Wnt inhibitors are routinely used to produce cardiomyocytes from pluripotent stem cells.[66][67]

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

c-myc, which control the G1 to S phase transition in the cell cycle. Entry into the S phase causes DNA replication and ultimately mitosis, which are responsible for cell proliferation.[68] 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.[69]

The biochemistry of cancer stem cells 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.[70]

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

myocytes, and tracheal cells.[71]

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.[72]

Insulin sensitivity

Diagram illustrating the interaction between the Wnt and insulin signaling pathways

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.[73]

Clinical implications

Cancer

Since its initial discovery, Wnt signaling has had an association with

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.[3]

Canonical Wnt pathway activity is involved in the development of

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.[77]

Wnt signaling has been implicated in the development of other cancers as well as in

Dact1.[81] Meanwhile Wnt is activated during the early outgrowth phase by E-selectin.[82]

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 carcinogenesis.[5]

Type II diabetes

Diabetes mellitus type 2 is a common disease that causes reduced insulin secretion and increased insulin resistance in the periphery. It results in increased blood glucose levels, or hyperglycemia, 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.[83] 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.[84] This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance.[85] Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are linked to increased susceptibility.[86]

See also

References

  1. S2CID 3189574
    .
  2. ^
    S2CID 10422968
    .
  3. ^
    PMID 15686623
    .
  4. PMID 20603214
    .
  5. ^
    PMID 19303855
    .
  6. PMID 15473860
    .
  7. ^
    PMID 19279717
    .
  8. PMID 28521071
    .
  9. S2CID 4261052
    .
  10. S2CID 31382024
    .
  11. PMID 9407023
    .
  12. PMID 26080277
    .
  13. PMID 24768165
    .
  14. PMID 22653731
    .
  15. S2CID 53009014
    .
  16. PMID 17117926
    .
  17. ^ Nusse, Roel. "The Wnt Homepage". Retrieved 15 April 2013.
  18. PMID 25263666
    .
  19. ^
    PMID 20576942
    .
  20. PMID 17884187
    .
  21. PMID 15720723
    .
  22. PMID 21859464
    .
  23. PMID 24130866
    .
  24. ^
    PMID 19619488
    .
  25. PMID 11920163
    .
  26. S2CID 16720801. Archived from the original
    (PDF) on 2021-09-26. Retrieved 2020-06-03.
  27. PMID 16630820
    .
  28. PMID 28296634
    .
  29. PMID 33085215
    .
  30. PMID 17287208
    .
  31. PMID 23637336
    .
  32. PMID 25184676
    .
  33. S2CID 6845295
    .
  34. PMID 16793760
    .
  35. PMID 21181886
    .
  36. ^
    S2CID 16120512
    .
  37. PMID 22771246
    .
  38. PMID 24158438
    .
  39. S2CID 16047397
    .
  40. PMID 23497616
    .
  41. PMID 25460271
    .
  42. PMID 24492943
    .
  43. PMID 27185050
    .
  44. PMID 25758784
    .
  45. ^
    PMID 30963603
    .
  46. PMID 21112773
    .
  47. PMID 30352677
    .
  48. PMID 27185050
    .
  49. PMID 31428581
    .
  50. PMID 21743455
    .
  51. S2CID 31357937
    .
  52. ^
    PMID 24130866
    .
  53. ^
    ISBN 9780878933846
    .
  54. PMID 20485500
    .
  55. ^ Gilbert SF (2014). "Early Development in Birds". Developmental Biology (10th ed.). Sunderland (MA): Sinauer Associates.
  56. PMID 19681160
    .
  57. S2CID 15635026
    .
  58. PMID 26965444
    .
  59. ISBN 978-981-4740-69-2
    .
  60. ^
    PMID 18392048
    .
  61. PMID 17711862
    .
  62. PMID 17875805
    .
  63. PMID 11159911
    .
  64. PMID 11159912
    .
  65. PMID 17522258
    .
  66. PMID 21737789
    .
  67. PMID 24930130
    .
  68. PMID 20059944
    .
  69. PMID 16751178
    .
  70. ^ Hodge, Russ (2016-01-25). "Hacking the programs of cancer stem cells". medicalxpress.com. Medical Express. Retrieved 2016-02-12.
  71. ^ Schambony A, Wedlich D (2013). Wnt Signaling and Cell Migration. Landes Bioscience. Retrieved 7 May 2013. {{cite book}}: |website= ignored (help)
  72. PMID 20490631
    .
  73. PMID 20041157
    .
  74. ^ Milosevic, V. et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.Int. J. Cancer, https://doi.org/10.1002/ijc.32419
  75. PMID 14739782
    .
  76. PMID 15054482
    .
  77. PMID 19549913
    .
  78. PMID 28261640
    .
  79. S2CID 35599667
    .
  80. PMID 27015306
    .
  81. PMID 33723425
    .
  82. PMID 30988423
    .
  83. S2CID 19299033
    .
  84. PMID 20634317
    .
  85. PMID 21239612
    .
  86. S2CID 28825825
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Wnt_signaling_pathway&oldid=1212907833"