Pathways & interactions
Frizzled/secreted frizzled-related protein (IPR015526)
Short name: Frizzled/SFRP
Overlapping homologous superfamilies
- Frizzled/secreted frizzled-related protein (IPR015526)
- Frizzled-1 (IPR026548)
- Frizzled-10 (IPR026549)
- Frizzled-2 (IPR026550)
- Frizzled-3, vertebrates (IPR026553)
- Frizzled-4 (IPR026551)
- Frizzled-6 (IPR026543)
- Frizzled-7 (IPR026552)
- Secreted frizzled-related protein 1 (IPR026559)
- Secreted frizzled-related protein 2 (IPR026558)
- Secreted frizzled-related protein 3 (IPR026556)
- Secreted frizzled-related protein 4 (IPR026560)
- Secreted frizzled-related protein 5 (IPR034860)
- Smoothened (IPR026544)
Frizzleds are seven transmembrane-spanning proteins that constitute an unconventional class of G protein-coupled receptors [PMID: 17884187]. They have important regulatory roles during embryonic development [PMID: 17884187, PMID: 21314612].
Frizzleds expose their large N terminus on the extracellular side. The N-terminal, extracellular cysteine-rich domain (CRD) has been implicated as the Wnt binding domain and its structure has been solved [PMID: 11452312]. The cysteine-rich domain of Frizzled (Fz) is shared with other receptor tyrosine kinases that have roles in development including the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. The cytoplasmic side of many Fz proteins has been shown to interact with the PDZ domains of PSD-95 family members and is thought to have a role in the assembly of signalling complexes. The conserved cytoplasmic motif of Fz, Lys-Thr-X-X-X-Trp, is required for activation of the beta-catenin pathway, and for membrane localisation and phosphorylation of Dsh.
In Drosophila melanogaster, the frizzled locus is involved in planar cell polarity, which is the coordination of the cytoskeleton of epidermal cells to produce a parallel array of cuticular hairs and bristles [PMID: 2174014, PMID: 2493583]. In the wild-type wing, all hairs point towards the distal tip [PMID: 2493583], whereas in Fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the developing wing, Fz function is required for cells to respond to the extracellular polarity signal as well as the proximal-distal transmission of an intracellular polarity signal.
In Caenorhabditis elegans, protein mom-5 is the equivalent of frizzled [PMID: 9288750].
Three main signaling pathways are activated by agonist-activated Frizzled proteins: the Fz/beta-catenin pathway, the Fz/Ca2+ pathway and the Fz/PCP (planar cell polarity) pathway [PMID: 17884187]. The Wnt/beta-catenin pathway is the best studied signalling pathway involving Fz receptors. In the Wnt/beta-catenin pathway the first downstream cytoplasmic components activated by Fz signalling include Dishevelled (Dsh) and/or its regulatory kinases.
There are secreted forms of Fz, known as soluble or secreted frizzled-related proteins (sFRPS), which function as modulators of Wnt signaling through direct interaction with Wnts [PMID: 10347172]. They consist of only the amino-terminal cysteine rich domain (CRD), but no transmembrane segments. These secreted forms may bind to Wnt proteins in solution and thereby change the activity of Wnts. Such as FRP/FrzB, which consist of the CRD only and can act as secreted antagonists of Wnt signalling.
This entry includes both frizzled proteins and secreted frizzled-related proteins (SFRP).
- PTHR11309 (PTHR11309)