The low density lipoprotein receptor-related proteins 5 and 6 (LPR5 and LPR6) serve as coreceptors with FzRs in the p-catenin pathway. LPR5 and LPR6 may also bind to secreted Dickkopf (Dkk) proteins that act as antagonists on the FzR-LRP complex by the formation of LPR5 and LPR6 complexes with another recently identified transmembrane receptor class (Kremen) which are internalized, making LPR5 and LPR6 unavailable for complexing with FzRs.105 As a consequence of the binding of Wnt to FzR-LRP complexes, p-catenin is stabilized, i.e., diverted from the proteosomes, and accumulates and enters nuclei where it binds to members of the TCF-LEF family of transcription factors, resulting in the activation of gene transcription.106 The plasma membrane recruitment of Dvl proteins by FzRs activated by Wnt family members is therefore a key intermediate step leading to the stabilization of p-catenin and activation of TCF/LEF transcription factors.93
The identification of both FzRs and LPRs 5 and 6 as components of cell surface receptors for Wnt proteins led to further investigations of their individual functions. Subsequently, it was found that LPR5-LPR6-Arrow proteins constitute distal signal-initiating components and that they are candidate oncogenes because their mutants may activate the Wnt/p-catenin pathway in a Frizzled and ligand-indepen-dent manner.107
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