The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome-dependent degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). Zinc and Ring Finger protein 1 (ZNRF1) is a member of the Really Interesting New Gene (RING) E3 protein ligase family and cloning of the human gene was first described by Araki et al. (2001). ZNRF1 has been shown to be expressed in both the central and peripheral nervous system of rats during development and in adulthood (Araki et al., 2001). Ube2D2 and Ube2D3 have been identified as supporting E2 conjugating enzymes in the in vitro ubiquitylation activity of ZNRF1 and mutation of the Zinc finger Ring finger domain of ZNRF1 showed that it was required for the E3 ligase activity of ZNRF1 (Araki and Milbrandt 2003). Over expression of ZNRF1 - which has been implicated in neuronal degeneration - has been shown to increase neurite outgrowth (Yoshida et al., 2009). ZNRF1 has also been shown to cause the degradation of the protein kinase AKT thus preventing the phosphorylation of glycogen synthase kinase-3β thus inactivating it in axons leading to Wallerian Degeneration (Wakatsuki et al., 2011).
Araki T, Nagarajan R, Milbrandt J. (2001) Identification of genes induced in peripheral nerve after injury: expression profiling and novel gene discovery. J Biol. Chem 276, 34131-34141.
Araki T, Milbrandt J. (2003) ZNRF proteins constitute a family of presynaptic E3 ubiquitin ligases J. Neurosci 23, 9385-9394.
Wakatsuki S, Saitoh F, Araki T. (2011) ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol 12, 1415-23.
Yoshida K, Watanabe M, Hatakeyama S. (2009) ZNRF1 interacts with tubulin and regulates cell morphogenesis Biochem Biophys Res Commun 389, 506-11.