CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

Abstract

All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle‐dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

Decoding the PTM-switchboard of Notch

“…From these S2513 and S2516 align with the previously found sites S2482 and 2485 on Xenopus laevis [ 110 ]. Furthermore, also CDK1 and CDK2 have been shown to phosphorylate S2513 leading to FBXW7-mediated degradation of N1-ICD, impacting the somite segmentation clock [ 112 ]. Taken together, the evidence points to an important role for Cyclin C and CDKs especially in controlling NICD turnover.…”

A quantised cyclin-based cell cycle model

“…The molecular weight of the cyclin proteins are known as cyclin A, B, E and D weigh 52 , 48, 50 and 34 kDa respectively. [24] From these weights and the concentrations of the recombinant proteins used to generate the standard curves, the number of protein molecules per cell were calculated varying from 1.2E 11 (10 ng) to 1.2E 12 (100 ng). The capabilities of such quantised simulations will allow for the ad hock threshold errors to be more accurately controlled; due to discrete countable systems having an error of , where N represents the number of molecules.…”

A tale of two clocks: phosphorylation of NICD by CDK s links cell cycle and segmentation clock

“…In this issue, Carrieri et al [1] show that phosphorylation of the Notch intracellular domain (NICD) by cyclin-dependent kinases (CDKs) suppresses Notch activity by promoting NICD turnover. In this issue, Carrieri et al [1] show that phosphorylation of the Notch intracellular domain (NICD) by cyclin-dependent kinases (CDKs) suppresses Notch activity by promoting NICD turnover.…”

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The Notch signaling pathway is tightly controlled via post-transcriptional regulatory mechanisms that promote or terminate pathway activity. In this issue, Carrieri et al [1] show that phosphorylation of the Notch intracellular domain (NICD) by cyclin-dependent kinases (CDKs) suppresses Notch activity by promoting NICD turnover. These findings link Notch pathway activity to the cell cycle, and the authors propose connections between this regulation and the segmentation clock that times embryonic somitogenesis.

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