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WNT signaling

Wnts are a class of evolutionarily-conserved, lipid-modified glycoproteins that play a pivotal role in development and homeostasis through a number of different paracrine and autocrine signal-transduction pathways. During early development, Wnt signaling plays a major role in axon guidance, cell polarity, and body axis specification. Extracellular Wnts bind a variety of different receptors, and initiate signaling in several distinct pathways. Receptors include seven-pass transmembrane Frizzleds and receptor tyrosine kinases ROR and Ryk.

Wnt signaling pathways can result in changes to gene transcription. For example, in the canonical β-catenin signaling pathway Wnt signaling prevents destruction of the transcriptional regulator β-catenin. Upon ligation to their receptors, the cytoplasmic protein disheveled (DVL) is recruited, phosphorylated and activated. Activation of DVL induces the dissociation of GSK-3β from Axin and leads to the inhibition of GSK-3β. Next, the phosphorylation and degradation of β-catenin is inhibited as a result of the inactivation of the "destruction complex". Subsequently, stabilized β-catenin translocates into the nucleus leading to changes in different target gene expressions. Wnt signaling can also prompt morphological changes to cellular structure e.g., the non-canonical planar cell polarity pathway induces a kinase cascade that results in reorganization of actin, a core component of the cytoskeleton. The non-canonical Wnt/Ca2+ pathways lead to release of intracellular Ca2+ via G-proteins. Elevated Ca2+ can activate the phosphatase calcineurin, which leads to dephosphorylation of the transcription factor NF-AT and its accumulation in the nucleus.

Genetic and epigenetic deregulation of Wnt/β-catenin signaling contributes to human cancer, which has led to the development of extensive approaches targeting Wnt/β-catenin signaling as cancer therapies. PORCN inhibitors, Wnt ligand antagonists, and FZD antagonists/monoclonal antibodies are beeing examined in clinical trials of various Wnt signaling-associated human cancers. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recent studies have identified several Wnt signaling regulators whose expression is specific to cancer cells. These cancer-specific regulatory processes of Wnt signaling may be druggable vulnerabilities of Wnt signaling-associated cancer.


References:

  1. Söderholm, S and Cantù, C (2021): "The WNT/β-catenin dependent transcription: A tissue-specific business " WIREs Mech Dis [PMID: 33085215]
  2. Zimmerli, D et al. (2020): "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex " Elife [PMID: 32808927]
  3. Patel, S et al. (2019): "Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights " Front Immunol https://doi.org/10.3389/fimmu.2019.02872doi: 10.4049/jimmunol.1900371
  4. Zimmerli, D et al. (2017): "Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein–protein interfaces of nuclear factors " Br J Pharmacol 174(24): 4600–4610. doi: 10.1111/bph.13864
  5. Komiya, Y et al. (2008): "Wnt signal transduction pathways" organogenesis, doi: 10.4161/org.4.2.5851
  6. Jung, Y et al., (2020): “Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex ” Experimental & Molecular Medicine, 52, pages 183–191 [DOI: nature]

Antagonists

APC2 (APC Regulator of WNT Signaling Pathway 2):

DKK4 (Dickkopf Homolog 4 (Xenopus Laevis)):

IGFBP4 (Insulin-Like Growth Factor Binding Protein 4):

IGFBP5 (Insulin-Like Growth Factor Binding Protein 5):

IGFBP6 (Insulin-Like Growth Factor Binding Protein 6):

KREMEN1 (Kringle Containing Transmembrane Protein 1):

KREMEN2 (Kringle Containing Transmembrane Protein 2):

SFRP1 (Secreted Frizzled-Related Protein 1):

SFRP2 (Secreted Frizzled-Related Protein 2):

SFRP4 (Secreted Frizzled-Related Protein 4):

SFRP5 (Secreted Frizzled-Related Protein 5):

(Secreted Xwnt8 Inhibitor Sizzled):

ZNRF3 (Zinc and Ring Finger Protein 3):

beta-Catenin Pathway

APC (Adenomatous Polyposis Coli):

TCF7L1 (Transcription Factor 7-Like 1 (T-Cell Specific, HMG-Box)):

TCF7L2 (Transcription Factor 7-Like 2 (T-Cell Specific, HMG-Box)):

AES (Amino-terminal Enhancer of Split):

CTNNB1 (Catenin (Cadherin-Associated Protein), beta 1, 88kDa):

DVL1 (Dishevelled Segment Polarity Protein 1):

GSK3b - GSK3 beta:

LLGL1 (Lethal Giant Larvae Homolog 1):

LLGL2 (Lethal Giant Larvae Homolog 2):

LEF1 (Lymphoid Enhancer-Binding Factor 1):

PYGO1 (Pygopus Homolog 1 (Drosophila)):

PYGO2 (Pygopus Homolog 2):

TBP (TATA Box Binding Protein):

TCF3 (Transcription Factor 3 (E2A Immunoglobulin Enhancer Binding Factors E12/E47)):

TCF7 (Transcription Factor 7 (T-Cell Specific, HMG-Box)):

TLE1 (Transducin-Like Enhancer of Split 1 (E(sp1) Homolog, Drosophila)):

TLE6 (Transducin-Like Enhancer of Split 6):

TLE2 (Transducin-Like Enhancer Protein 2):

TLE4 (Transducin-like Enhancer Protein 4):

Calcium Pathway

CAMK2B (Calcium/calmodulin-Dependent Protein Kinase II beta):

CAMK2A (Calcium/calmodulin-Dependent Protein Kinase II alpha):

CDC42 (Cell Division Cycle 42 (GTP Binding Protein, 25kDa)):

PPP3CA (Protein Phosphatase 3, Catalytic Subunit, alpha Isoform):

CAMK2D (Calcium/calmodulin-Dependent Protein Kinase II delta):

PLCB3 (phospholipase C, beta 3 (Phosphatidylinositol-Specific)):

PLCD1 (phospholipase C, delta 1):

PPP3CB (Protein Phosphatase 3, Catalytic Subunit, beta Isozyme):

PPP3CC (Protein Phosphatase 3, Catalytic Subunit, gamma Isozyme):

PPP3R1 (Protein Phosphatase 3, Regulatory Subunit B, alpha):

Co-Receptors

LRP5 (Low Density Lipoprotein Receptor-Related Protein 5):

LRP6 (Low Density Lipoprotein Receptor-Related Protein 6):

RYK (RYK Receptor-Like Tyrosine Kinase):

LGR5 (Leucine-Rich Repeat Containing G Protein-Coupled Receptor 5):

RNF43 (Ring Finger Protein 43):

Frizzleds

FZD2 (Frizzled Family Receptor 2):

GPBAR1 (G Protein-Coupled Bile Acid Receptor 1):

HYFZD5/8 - Frizzled5/8:

FZD9 (Frizzled Family Receptor 9):

FZD8 (Frizzled Family Receptor 8):

FZD7 (Frizzled Family Receptor 7):

FZD6 (Frizzled Family Receptor 6):

FZD5 (Frizzled Family Receptor 5):

FZD4 (Frizzled Family Receptor 4):

FZD3 (Frizzled Family Receptor 3):

FZD10 (Frizzled Family Receptor 10):

LOC100313610 - Frizzled 5/8 Protein Receptor:

(Frizzled 1/2/7):

(Frizzled):

PCP Pathway

DAAM1 (Dishevelled Associated Activator of Morphogenesis 1):

MAPK10 (Mitogen-Activated Protein Kinase 10):

NFAT5 (Nuclear Factor of Activated T-Cells 5, Tonicity-Responsive):

NFATC1 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 1):

NFAT1 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 2):

NFATC3 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 3):

NFATC4 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 4):

PRICKLE1 (Prickle-Like Protein 1):

(RAC1+CDC42):

RHOA (Ras Homolog Gene Family, Member A):

RHOC (Ras Homolog Gene Family, Member C):

ROCK1 (rho-Associated, Coiled-Coil Containing Protein Kinase 1):

ROCK2 (rho-Associated, Coiled-Coil Containing Protein Kinase 2):

Receptor Tyrosine Kinases

ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1):

ROR2 (Receptor Tyrosine Kinase-Like Orphan Receptor 2):

RYK (RYK Receptor-Like Tyrosine Kinase):

WNTs

WNT2 (Wingless-Type MMTV Integration Site Family Member 2):

WNT1 (Wingless-Type MMTV Integration Site Family, Member 1):

WNT10A (Wingless-Type MMTV Integration Site Family, Member 10A):

WNT10B (Wingless-Type MMTV Integration Site Family, Member 10B):

WNT11 (Wingless-Type MMTV Integration Site Family, Member 11):

WNT16 (Wingless-Type MMTV Integration Site Family, Member 16):

WNT2B (Wingless-Type MMTV Integration Site Family, Member 2B):

WNT3 (Wingless-Type MMTV Integration Site Family, Member 3):

WNT3A (Wingless-Type MMTV Integration Site Family, Member 3A):

WNT4 (Wingless-Type MMTV Integration Site Family, Member 4):

WNT5A (Wingless-Type MMTV Integration Site Family, Member 5A):

WNT5B (Wingless-Type MMTV Integration Site Family, Member 5B):

WNT6 (Wingless-Type MMTV Integration Site Family, Member 6):

WNT7A (Wingless-Type MMTV Integration Site Family, Member 7A):

WNT7B (Wingless-Type MMTV Integration Site Family, Member 7B):

WNT8A (Wingless-Type MMTV Integration Site Family, Member 8A):

WNT8B (Wingless-Type MMTV Integration Site Family, Member 8B):

WNT9A (Wingless-Type MMTV Integration Site Family, Member 9A):

WNT9B (Wingless-Type MMTV Integration Site Family, Member 9B):

(Wnt 7a/b):

WISP1 (WNT1 Inducible Signaling Pathway Protein 1):

WISP2 (WNT1 Inducible Signaling Pathway Protein 2):

WISP3 (Wnt1 Inducible Signaling Pathway Protein 3):

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