Why cyclin Y? A highly conserved cyclin with essential functions.

Abstract

Cyclin Y is one of the most highly conserved members of the cyclin superfamily of proteins, which are famous for their crucial roles in regulating the cell cycle and transcription. Despite this high degree of conservation, very little was known about Cyclin Y function prior to a handful of studies published in this past year. Cyclins typically function by activating cyclin-dependent kinases (Cdks) and one insight has come from the identification of a Cdk that is activated by Cyclin Y. Yeast two-hybrid data first linked Cyclin Y with Cdk14, known as Eip63E in Drosophila or PFTAIRE1 in vertebrates. In Drosophila, both Cyclin Y and Eip63E are essential at many stages of development, from embryogenesis to metamorphosis and null mutants show a similar spectrum of developmental defects. In cultured cells, Cyclin Y and Eip63E were shown to phosphorylate the Wg/Wnt co-receptor Arrow/LRP6 in a ligand-independent manner. Eip63E is recruited to LRP6 at the plasma membrane by interacting with Cyclin Y, which is tethered to the membrane through an N-terminal myristoylation. Cyclin Y-dependent LRP6 phosphorylation appears to prime the receptor for subsequent ligand-dependent phosphorylation and activation of the canonical Wnt signaling pathway. Interestingly, Wnt receptor phosphorylation and signaling is maximal in G₂/M when Cyclin Y is at its highest levels, suggesting that Cyclin Y may serve to entrain Wnt signaling to the cell cycle. Given the wide range of roles for Wnt signaling during development, these studies may help explain why Cyclin Y is required at several developmental stages and in turn why these proteins are so well conserved in metazoans.