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WNT Signaling

Written/Edited by Julian Pampel, BSc

Wnts are a class of evolutionarily conserved, lipid-modified glycoproteins that play a pivotal role in development and homeostasis through several 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 various different receptors and initiate signaling in several distinct pathways. Receptors include seven-pass transmembrane Frizzleds and receptor tyrosine kinases ROR and Ryk.

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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 are 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 the reorganization of actin, a core component of the cytoskeleton. The non-canonical Wnt/Ca²⁺ pathways lead to a 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 various human cancers, prompting the development of targeted therapies. PORCN inhibitors, Wnt ligand antagonists, and FZD antagonists/monoclonal antibodies are currently being tested in clinical trials for Wnt-related cancers. However, blocking Wnt signaling can lead to side effects, including disruption of tissue homeostasis and regeneration. Recent studies have identified cancer-specific Wnt signaling regulators, presenting druggable vulnerabilities that offer new therapeutic opportunities. Antibodies-online provides a broad range of antibodies targeting key components of the Wnt signaling pathway, supporting research in this critical area.

References:

Söderholm, Cantù: "The WNT/β-catenin dependent transcription: A tissue-specific business." in: WIREs mechanisms of disease, Vol. 13, Issue 3, pp. e1511, (2022) (PubMed).
Zimmerli, Borrelli, Jauregi-Miguel, Söderholm, Brütsch, Doumpas, Reichmuth, Murphy-Seiler, Aguet, Basler, Moor, Cantù: "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex." in: eLife, Vol. 9, (2021) (PubMed).
Patel, Alam, Pant, Chattopadhyay: "Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights." in: Frontiers in immunology, Vol. 10, pp. 2872, (2020) (PubMed).
Zimmerli, Hausmann, Cantù, Basler: "Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors." in: British journal of pharmacology, Vol. 174, Issue 24, pp. 4600-4610, (2018) (PubMed).
Komiya, Habas: "Wnt signal transduction pathways." in: Organogenesis, Vol. 4, Issue 2, pp. 68-75, (2012) (PubMed).
Jung, Park: "Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex." in: Experimental & molecular medicine, Vol. 52, Issue 2, pp. 183-191, (2021) (PubMed).

Antagonists

DKK1 (Dickkopf Homolog 1):

APC2 (APC Regulator of WNT Signaling Pathway 2):

APC2 Antibodies

DKK2 (Dickkopf 2 Homolog):

DKK4 (Dickkopf Homolog 4 (Xenopus Laevis)):

FRZB (Frizzled-Related Protein):

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):

WIF1 (WNT Inhibitory Factor 1):

ZNRF3 (Zinc and Ring Finger Protein 3):

beta-Catenin Pathway

APC (Adenomatous Polyposis Coli):

CSNK1A1 (Casein Kinase 1, alpha 1):

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):

AXIN1 - Axin:

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

DVL1 (Dishevelled Segment Polarity Protein 1):

GSK3a - GSK3 alpha:

GSK3b - GSK3 beta:

GSK3 beta Antibodies

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)):

TCF4 (Transcription Factor 4):

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):

TLE4 Antibodies

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):

CAMK2G - CAMKII gamma:

PLCb2 - Phospholipase C beta 2:

PLCb4 - Phospholipase C beta 4:

PLCd3 - Phospholipase C delta 3:

PLCG2 - Phospholipase C gamma 2:

PLCB1 - Phospholipase C beta 1:

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

PLCD1 (phospholipase C, delta 1):

PLCG1 - Phospholipase C gamma 1:

PKCa - PKC alpha:

PRKCB - PKC beta:

PRKCG - PKC gamma:

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):

CDH1 - E-cadherin:

RYK (RYK Receptor-Like Tyrosine Kinase):

VANGL2 (Vang-Like 2):

Vangl1 (Vang-Like 1):

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

RNF43 (Ring Finger Protein 43):

Frizzleds

Fzd1 - FZD1:

FZD2 (Frizzled Family Receptor 2):

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

HYFZD5/8 - Frizzled5/8:

Show all Frizzled5/8 products

FZD9 (Frizzled Family Receptor 9):

FZD8 (Frizzled Family Receptor 8):

FZD7 (Frizzled Family Receptor 7):

FZD7 Antibodies

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):

JUN - C-JUN:

RHO - Rhodopsin:

MAPK10 (Mitogen-Activated Protein Kinase 10):

MAPK8 - JNK:

MAPK9 - JNK2:

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:

(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):

RHO - Rhodopsin:

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):

WNT8B Antibodies

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):

WLS - GPR177/WLS:

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