Abstract
The fission yeast scaffold molecule Sid4 anchors the septum initiation network to the spindle pole body (SPB, centrosome equivalent) to control mitotic exit events. A second SPB-associated scaffold, Cut12, promotes SPB-associated Cdk1-cyclin B to drive mitotic commitment. Signals emanating from each scaffold have been assumed to operate independently to promote two distinct outcomes. We now find that signals from Sid4 contribute to the Cut12 mitotic commitment switch. Specifically, phosphorylation of Sid4 by NIMAFin1 reduces Sid4 affinity for its SPB anchor, Ppc89, while also enhancing Sid4's affinity for casein kinase 1δ (CK1δ). The resulting phosphorylation of Sid4 by the newly docked CK1δ recruits Chk2Cds1 to Sid4. Chk2Cds1 then expels the Cdk1-cyclin B antagonistic phosphatase Flp1/Clp1 from the SPB. Flp1/Clp1 departure can then support mitotic commitment when Cdk1-cyclin B activation at the SPB is compromised by reduction of Cut12 function. Such integration of signals emanating from neighboring scaffolds shows how centrosomes/SPBs can integrate inputs from multiple pathways to control cell fate.
Highlights
Cdk1–cyclin B activity is restrained through Wee1 kinase phosphorylation of Cdk1 until Cdc25 phosphatase removes this phosphate to promote mitosis
When Cut12 function is compromised by shifting the temperaturesensitive cut12.1 mutant to the restrictive temperature of 36°C, PoloPlo1 activity falls, and the new spindle pole body (SPB), which has been generated by conservative duplication, fails to nucleate microtubules, leading to cell cycle arrest with a monopolar spindle (Fig. 1 A; Bridge et al, 1998; MacIver et al, 2003; Tallada et al, 2009)
All soc mutations resided in the C-terminal septum initiation defective (SID) domain (Pfam 11778) that anchors Sid4 to the core SPB component Ppc89 (Fig. 1, E and F; Tomlin et al, 2002; Morrell et al, 2004; Rosenberg et al, 2006). cut12.1 suppression by sid4.13myc and sid4.TdTom alleles in which the tag had been fused to the C terminus of Sid4 (Krapp et al, 2001; Grallert et al, 2006) further highlighted the ability of changes in the carboxyl terminal region of the mitotic exit anchor Sid4 to compensate for local Cdk1–cyclin B activation deficiency in mitotic commitment of cut12.1 (Fig. 1 D). sid4.GFP did not suppress cut12.1
Summary
Cdk1–cyclin B activity is restrained through Wee kinase phosphorylation of Cdk until Cdc phosphatase removes this phosphate to promote mitosis. When Cut function is compromised by shifting the temperaturesensitive cut12.1 mutant to the restrictive temperature of 36°C, PoloPlo activity falls, and the new SPB, which has been generated by conservative duplication, fails to nucleate microtubules, leading to cell cycle arrest with a monopolar spindle (Fig. 1 A; Bridge et al, 1998; MacIver et al, 2003; Tallada et al, 2009) The activation of this nonfunctional SPB by enhancement of Cdc levels shows that the inactivity of the new SPB arises from a failure to locally activate Cdk1–cyclin B on this
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