Frizzled proteins are a family of cell surface receptors that act as receivers for external signals. They are fundamental to cellular communication, enabling cells to interpret and respond to their environment. Found across diverse animal species, Frizzled proteins coordinate numerous biological processes, highlighting a conserved mechanism for relaying messages that influence cell behavior and development.
Understanding Frizzled Proteins
Frizzled proteins are a family of cell surface receptors characterized by their unique structure. Each Frizzled protein typically spans the cell membrane seven times, featuring an extracellular N-terminus with a specialized cysteine-rich domain (CRD). This CRD is responsible for binding to specific signaling molecules. The intracellular C-terminal domain, while variable, transmits signals inside the cell. There are ten known human Frizzled receptors, ranging from approximately 500 to 700 amino acids in length. These receptors detect cues from outside the cell, initiating internal events that translate external messages into cellular actions.
The Wnt-Frizzled Signaling Pathway
Frizzled proteins are central to the Wnt signaling pathway, which orchestrates cellular responses. This pathway begins when Frizzled receptors bind to Wnt ligands, secreted glycoproteins. This binding often involves Frizzled interacting with co-receptors like LRP5 or LRP6, forming a complex that initiates signal transduction.
Upon Wnt ligand binding, Frizzled receptors undergo conformational changes, leading to the recruitment and activation of Dishevelled (Dvl). In the canonical Wnt/β-catenin pathway, activated Dvl interferes with a “destruction complex” (Axin, APC, casein kinase 1α, and GSK3). Normally, this complex phosphorylates β-catenin for degradation.
However, active Wnt signaling inhibits the destruction complex, preventing β-catenin degradation. This allows β-catenin to accumulate in the cytoplasm and translocate into the cell nucleus. In the nucleus, β-catenin associates with TCF/LEF transcription factors, activating specific Wnt target genes like c-myc and cyclin D1, which influence cell proliferation.
Frizzled proteins also participate in non-canonical Wnt pathways, such as the Wnt/planar cell polarity (PCP) pathway and the Wnt/calcium (Wnt/Ca²⁺) pathway. In the PCP pathway, Wnt-Frizzled binding activates Rho and Rac GTPases, which activate effectors like ROCK and JNK, causing cytoskeletal reorganization. The Wnt/Ca²⁺ pathway, distinct from β-catenin signaling, increases intracellular calcium levels and activates protein kinase C, influencing transcription factors like NFκB and CREB.
Frizzled’s Diverse Roles in Biology
Through Wnt signaling, Frizzled proteins regulate numerous biological processes in healthy organisms. During embryonic development, Frizzled activity patterns tissues, guides cell differentiation, and shapes organ formation. For example, Frizzled genes are crucial for the proper orientation of structures like cuticular hairs and bristles in Drosophila, demonstrating their role in tissue polarity.
Frizzled signaling also maintains stem cells, ensuring their self-renewal and differentiation. This influence extends to tissue regeneration, where Frizzled-mediated pathways contribute to the repair and renewal of damaged tissues. Frizzled proteins are also involved in establishing cell polarity, which dictates asymmetric cell organization, and guiding cell migration, important for tissue development and wound healing.
When Frizzled Goes Wrong: Disease Connections
Dysfunction in Frizzled proteins or the Wnt signaling pathway can contribute to various diseases. Aberrant Wnt activation, often due to mutations or abnormal expression of Frizzled receptors, is common in several cancers. For instance, in colorectal cancers, issues with kinases or phosphatases regulating Frizzled phosphorylation can lead to excessive Wnt/β-catenin activity, driving tumor proliferation.
Specific Frizzled receptors can be overexpressed in certain cancers, promoting malignant behaviors. Frizzled10, for example, is minimally expressed in most adult tissues but overexpressed in synovial sarcoma and hepatocellular carcinoma, contributing to tumor progression. Beyond cancer, Frizzled signaling disruptions have been linked to developmental disorders, such as familial exudative vitreoretinopathy, a rare retinal condition associated with Frizzled-4 receptor mutations. Dysregulated Wnt signaling, involving Frizzled receptors, has also been implicated in neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, and metabolic disorders like obesity and insulin resistance.