Canonical Wnt Signaling Pathway

Wnt proteins are secreted, lipid-modified glycoproteins named from a portmanteau of the Wingless gene in Drosophila and the Integrated gene in vertebrates. Humans have 19 different Wnt proteins that regulate a conserved signaling pathway controlling critical developmental events including cell fate determination, cell motility, polarity, organogenesis, and stem cell renewal.

In the canonical Wnt β-catenin pathway, Wnt protein binding to Frizzled and LRP receptors interrupts the degradation complex through dishevelled, preventing β-catenin phosphorylation and ubiquitination. This increases cytoplasmic β-catenin levels, allowing it to translocate into the nucleus where it binds transcriptional factors and induces Wnt target gene expression.

Frizzled receptors are transmembrane proteins that, along with coreceptors like low-density lipoprotein related proteins (LRPs), mediate signaling in target cells across all three Wnt pathways. The Wnt protein binds to these receptors to form a Wnt-Frizzled-coreceptor complex, initiating downstream signaling cascades.

Two prominent Wnt target genes are cyclin D1 and c-myc, both oncogenes that regulate cell growth, proliferation, and cell death. Their overexpression due to abnormal Wnt signaling can lead to uncontrolled cell growth and cancer progression, particularly in colorectal cancers where aberrant Wnt signaling is the primary cause.

Beta-catenin plays dual roles: it regulates gene transcription when translocated to the nucleus during canonical Wnt signaling, and it is a crucial component of the cadherin-catenin-actin complex during cell-cell adhesion. These functions make it central to both developmental signaling and cellular structural integrity.

Dysregulation of Wnt signaling is linked to colorectal cancer, bone diseases, cardiovascular diseases, and recent evidence supports its role in aging brain function and Alzheimer's disease. Given Wnt's crucial role in embryonic development and adult tissue homeostasis, aberrant signaling disrupts normal intercellular communication and tissue maintenance.

The canonical Wnt β-catenin pathway regulates beta-catenin breakdown and gene transcription, while non-canonical pathways are beta-catenin independent and use different secondary messengers. However, recent discoveries show these pathways are not autonomous and have considerable overlap and crosstalk between them, making them interconnected.