XB-ART-56907Semin Cell Dev Biol 2020 Nov 01;107:21-27. doi: 10.1016/j.semcdb.2020.03.010.
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Cyclin-dependent kinases (CDKs) require the binding to a regulatory subunit to acquire enzymatic activity, and cyclins are the canonical CDK activators. However, there are specific situations in which CDKs can be activated by non-cyclin proteins that are less characterized. This review focuses on the family of RINGO/Speedy proteins, which have no sequence amino acid homology to cyclins but can bind to and activate CDK1 and CDK2. Interestingly, RINGO/Speedy proteins can activate CDKs under conditions in which CDK-cyclin complexes would not be active, and there is evidence that RINGO/Speedy-activated CDKs can phosphorylate different sites than the cyclin-activated CDKs. RINGO/Speedy proteins were originally described in Xenopus oocytes, but their roles in mammalian cells have also been addressed. We will summarize the properties of RINGO/Speedy proteins and how they trigger CDK activation, and discuss recent studies that characterized their physiological functions. In particular, studies using genetically modified mice have shown that RingoA, also known as Spy1, plays a key role in meiosis regulation. Emerging evidence also suggests a potential role for RingoA/Spy1 in cancer.
PubMed ID: 32317145
Article link: Semin Cell Dev Biol
Species referenced: Xenopus laevis
Genes referenced: cdk1 cdk2 cdkn1b myt1 nedd4 siah1 skp2 spdya
Disease Ontology terms: cancer
Article Images: [+] show captions
|Fig. 1. Mechanisms that regulate the function of RINGO/Speedy proteins. Binding of RINGO/Speedy proteins to CDK1 and CDK2 suffices to induce activation of these kinases under conditions in which CDK-cyclin complexes would not be active. In particular, CDK-RINGO/Speedy complexes are equally active regardless of the CDK phosphorylation on the T-loop, are less affected by the p21Cip1 and p27Kip1 CDK inhibitors, and are able to phosphorylate and inhibit the CDK negative regulators p27Kip1 and Myt1. The E3 ubiquitin ligases Skp2 and NEDD4 can interact with and induce the degradation of the overexpressed RingoA/Spy1, while SCFβTrcP and Siah-2 regulate XRINGO processing and degradation, respectively. Gray symbols indicate whether the links have been made using mammalian RingoA/Spy1 or Xenopus XRINGO.|