Abstract
Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.
Highlights
The frizzled receptors (FZDs) are comprised of ten members (FZD1–FZD10)
Other heterodimeric receptor complexes comprised of an FZD and the cell surface receptors encoded by the receptor tyrosine kinase like orphan receptor 2 (ROR2) and receptor-like tyrosine kinase (RYK) genes have been described [2]
As a crucial component of WNT signaling pathway, the FZD family anchored in cell membrane functions in binding to extracellular WNT ligands and transmitting WNT signals to the intracellular molecules, which results in the increased transcription of target genes, many of which encode known oncogenes
Summary
The frizzled receptors (FZDs) are comprised of ten members (FZD1–FZD10). The common characteristics of these members include an N-terminal signal sequence followed by highly conserved cysteine-rich domain (CRD) in extracellular region, a seven-pass transmembrane domain and an intracellular C-terminal domain [1]. The intracellular C-terminal domain of FZDs interacts with the Dishevelled (DVL) protein to transduce the WNT signals to the downstream of the pathway [3]. Each member of FZDs can interact with several different WNT proteins to activate either the canonical WNT/β-catenin or the non-canonical WNT/PCP (planar cell polarity) and WNT/Ca2+ signaling pathways [4], thereby activating multiple downstream transcription factors that are important for stem cell regulation, embryonic development, cell polarity, proliferation and differentiation, and especially tumorigenesis [5,6]. FZDs function as cell surface receptors of WNT signaling pathway. If FZDs are blocked by antibodies or small molecule inhibitors, the WNT signaling pathway will not be activated so that those downstream target genes (e.g., CCND1, MYC) will not be activated as well. We aim to focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers
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