Cks confers specificity to phosphorylation-dependent CDK signaling pathways

McGrath, D.A.; Balog, Eva Rose M.; Kõivomägi, Mardo; Lucena, Rafael; Mai, Michelle V; Hirschi, Alexander; Kellogg, Douglas R.; Loog, Mart; Rubin, Seth M.

doi:10.1038/nsmb.2707

Cited by 87 publications

(134 citation statements)

References 52 publications

(86 reference statements)

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“…For example, the response of Cdc25C to Cdk1 is more highly ultrasensitive than one would obtain from a non-cooperative multisite phosphorylation mechanism (Fig 1C). Moreover, Cdc25C possesses phosphorylation sites that conform well to the Cks binding consensus (T48, T67, and T138), and elimination of these sites changes the response of Cdc25C from ultrasensitive to Michaelian (Fig 1C) [9, 12]. These results suggest that priming generates cooperativity and cooperativity contributes to the highly ultrasensitive response seen in this system.…”

Section: Priming and Cooperativity In Multisite Phosphorylationmentioning

confidence: 83%

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Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback

Ferrell

2014

Trends in Biochemical Sciences

195

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In this series of reviews we are examining ultrasensitive responses, the switch-like input-output relationships that contribute to signal processing in a wide variety of signaling contexts. In the first part of this series we examined one mechanism for generating ultrasensitivity, zero-order ultrasensitivity, where the saturation of two converting enzymes allows the output to switch from low to high over a tight range of input levels. In this second installment, we focus on three conceptually distinct mechanisms for ultrasensitivity: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. We also examine several related mechanisms and concepts, including cooperativity, reciprocal regulation, coherent feedforward regulation, and substrate competition, and provide several examples of signaling processes where these mechanisms are known or are suspected to be applicable.

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Section: Priming and Cooperativity In Multisite Phosphorylationmentioning

confidence: 83%

“…The phosphorylation of the first Thr (T) site primes the substrate for phosphorylation of the second Ser (S) residue as a result of the interaction of the pThr epitope with the Cks subunit, and can make the second phosphorylation be more favorable than the first. Adapted from [12]. …”

Section: Figmentioning

confidence: 99%

Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback

Ferrell

2014

Trends in Biochemical Sciences

195

206

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“…These results imply that Far1 inhibits substrate docking strongly, with a residual effect on some non-docking function such as Cdk kinase activity. This residual effect might also signify a reduction in kinase processivity mediated by the Cks1 subunit of the Cdk complex [18–20], though it was still evident when the role of Cks1 was blocked (by changing threonine phosphorylation sites to serine; Figure S4D). It is also notable that this residual effect was only seen with the G1/S cyclins Cln1 and Cln2 (Figure 4D), even though Far1-S87A could bind all cyclins (Figure 4E).…”

Section: Resultsmentioning

confidence: 99%

“…This mutant also revealed that inhibitory effects of Far1 are at least partly independent of T306 phosphorylation. Yet, T306 phosphorylation makes Far1 a more potent inhibitor, likely via enhanced binding to Cdk complexes [5] and possibly via engaging the phospho-threonine binding pocket in Cks1 [19, 20]. …”

Section: Discussionmentioning

confidence: 99%

Regulation of Cyclin-Substrate Docking by a G1 Arrest Signaling Pathway and the Cdk Inhibitor Far1

2014

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Summary Eukaryotic cell division is often regulated by extracellular signals. In budding yeast, signaling from mating pheromones arrests the cell cycle in G1 phase [1]. This arrest requires the protein Far1 [2], which is thought to antagonize the G1/S transition by acting as a Cdk inhibitor (CKI) [3, 4], although the mechanisms remain unresolved [5]. Recent studies found that G1/S cyclins (Cln1 and Cln2) recognize Cdk substrates via specific docking motifs, which promote substrate phosphorylation in vivo [6, 7]. Here, we show that these docking interactions are inhibited by pheromone signaling, and that this inhibition requires Far1. Moreover, Far1 mutants that cannot inhibit docking are defective at cell cycle arrest. Consistent with this arrest function, Far1 outcompetes substrates for association with G1/S cyclins in vivo, and it is present in large excess over G1/S cyclins during the pre-commitment period where pheromone can impose G1 arrest. Finally, a comparison of substrates that do and do not require docking suggests that Far1 acts as a multi-mode inhibitor that antagonizes both kinase activity and substrate recognition by Cln1/2-Cdk complexes. Our findings uncover a novel mechanism of Cdk regulation by external signals, and shed new light on Far1 function to provide a revised view of cell cycle arrest in this model system.

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“…In vitro, the docking function of Cln2 was required for multi-site phosphorylation of substrates, which involves processive catalysis and the Cks1 subunit of the cyclin-CDK-Cks1 complex [15, 42]. Thus, in vivo, events that require extensive substrate phosphorylation may be especially dependent on docking, and this could underlie some functional distinctions among G1 cyclins.…”

Section: Discussionmentioning

confidence: 99%

A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

et al. 2015

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Summary Background Eukaryotic cell division is driven by cyclin-dependent kinases (CDKs). Distinct cyclin-CDK complexes are specialized to drive different cell cycle events, though the molecular foundations for these specializations are only partly understood. In budding yeast, the decision to begin a new cell cycle is regulated by three G1 cyclins (Cln1–Cln3). Recent studies revealed that some CDK substrates contain a novel docking motif that is specifically recognized by Cln1 and Cln2, and not by Cln3 or later S- or M-phase cyclins, but the responsible cyclin interface was unknown. Results Here, to explore the role of this new docking mechanism in the cell cycle, we first show that it is conserved in a distinct cyclin subtype (Ccn1). Then, we exploit phylogenetic variation to identify cyclin mutations that disrupt docking. These mutations disrupt binding to multiple substrates as well as the ability to use docking sites to promote efficient, multi-site phosphorylation of substrates in vitro. In cells where the Cln2 docking function is blocked, we observed reductions in the polarized morphogenesis of daughter buds and reduced ability to fully phosphorylate the G1/S transcriptional repressor Whi5. Furthermore, disruption of Cln2 docking perturbs the coordination between cell size and division, such that the G1/S transition is delayed. Conclusions The findings point to a novel substrate interaction interface on cyclins, with patterns of conservation and divergence that relate to functional distinctions among cyclin subtypes. Furthermore, this docking function helps ensure full phosphorylation of substrates with multiple phosphorylation sites, and this contributes to punctual cell cycle entry.

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Cks confers specificity to phosphorylation-dependent CDK signaling pathways

Cited by 87 publications

References 52 publications

Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback

Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback

Regulation of Cyclin-Substrate Docking by a G1 Arrest Signaling Pathway and the Cdk Inhibitor Far1

A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

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