Redundant targeting of Isr1 by two CDKs in mitotic cells
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MINI-REVIEW
Redundant targeting of Isr1 by two CDKs in mitotic cells Emma B. Alme1 · David P. Toczyski1 Received: 13 September 2020 / Revised: 13 September 2020 / Accepted: 17 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Protein phosphorylation is an essential regulatory mechanism that controls most cellular processes, integrating a variety of environmental signals to drive cellular growth. Isr1 is a negative regulator of the hexosamine biosynthesis pathway (HBP), which produces UDP-GlcNAc, an essential carbohydrate that is the building block of N-glycosylation, GPI anchors and chitin. Isr1 was recently shown to be regulated by phosphorylation by the nutrient-responsive CDK kinase Pho85, allowing it to be targeted for degradation by the S CFCDC4. Here, we show that while deletion of PHO85 stabilizes Isr1 in asynchronous cells, Isr1 is still unstable in mitotically arrested cells in a pho85∆ strain. We provide evidence to suggest that this is through phosphorylation by CDK1. Redundant targeting of Isr1 by two distinct kinases may allow for tight regulation of the HBP in response to different cellular signals. Keywords ISR1 · CDC4 · PHO85 · CDK1 · GFA1
Introduction In all eukaryotes, cell-cycle regulation is driven by a set of cyclin-dependent kinases that contain a catalytic subunit (a CDK) and a cyclin. One way in which this cyclin CDK complex is regulated is through the periodic destruction of the cyclin subunit. The budding yeast Saccharomyces cerevisiae encodes a single essential CDK whose catalytic subunit, called Cdk1 (or Cdc28), associates with any of nine cyclins (Morgan 2007). While this is the only CDK required for cell-cycle regulation, another CDK, called Pho85 also promotes cell-cycle progression and associates with cell cycle regulated cyclins, known as Pcls (Carroll et al. 2001; Huang et al. 2007). One such example is Pcl1, which is active in G1 (Espinoza et al. 1994). In addition to cell-cycle regulated Pcls, Pho85 can also associated with several Pcls regulated by changes in nutrients, such as glycogen levels (Huang et al. 1998). Both Cdk1 and Pho85 utilize a proline directed consensus sites (S/T-P) (O’Neill et al. 1996; Holt et al. 2009).
Communicated by M. Kupiec. * David P. Toczyski [email protected] 1
Department of Biochemistry, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
One well-characterized function of CDK1 is targeting substrates for degradation by the SCF. The SCF is a ubiquitin ligase composed of several core subunits, including a cullin and RING subunit, and any of several specificity subunits called F box proteins (Willems et al. 2004). Two of these F box proteins, Cdc4 and Grr1, have been shown to specifically recognize proteins once they have been phosphorylated (Skowyra et al. 1997; Lyons et al. 2013). While these F box proteins do target proteins after phosphorylation by other kinases, such as Snf1 in the case of Grr1 (Benanti et al. 2007), most Cdc4 and Grr1 substrates are
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