Switching cyclin D-Cdk4 kinase activity on and off

Abstract

The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extraceullar environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, we have recently shown that p27 can be both a cdk4 bound-inhibitor and a bound-non-inhibitor, depending on the growth state of the cell. This perspective highlights the significance of this finding in terms of normal cell cycle progression and tumor development.

Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment

“…The mTOR pathway regulates translation of cyclin D1 mRNA. The major function of cyclin D1 is to integrate stimuli from extracellular mitogenic factors, such as tyrosine kinases and hormones, with cell-cycle progression during the G1 phase (reviewed in Blain, 2008). Interestingly, cyclin D1 expression is increased in …”

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

“…p27 tyrosine phosphorylation regulates the activity of Cdk4/cyclin D and Cdk6/cyclin D complexes in early G 1 phase. Phosphorylation of Tyr88 relieves Cdk4(6) inhibition but also allows p27 to remain bound to and stabilize these complexes, providing an explanation for how p27 can serve as an assembly factor for Cdk4/cyclin D and Cdk6/cyclin D complexes (Blain , 2008 ). p21 and p27 are representative examples of IDPs that function as scaffolds for the assembly of multiprotein complexes, in which interaction motifs within their extended structure mediate the specifi c assembly process.…”

p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes

“…This protein was originally considered as a 'universal' inhibitor of cyclin-cdk complexes whose activity was exerted by the N-terminal half of the molecule (Russo et al, 1996). However, recent reports revealed a dual role of p27, behaving as an inhibitor or and activator of cyclin D-cdk4/6 and cyclin E-cdk2 on depending of specific tyrosine phosphorylation (Chu et al, 2007;Grimmler et al, 2007;Blain, 2008;James et al, 2008). p27 deficiency is associated with tumorigenesis.…”