Regulation of CDK4

Abstract

Cyclin-dependent kinase (CDK)4 is a master integrator that couples mitogenic and antimitogenic extracellular signals with the cell cycle. It is also crucial for many oncogenic transformation processes. In this overview, we address various molecular features of CDK4 activation that are critical but remain poorly known or debated, including the regulation of its association with D-type cyclins, its subcellular location, its activating Thr172-phosphorylation and the roles of Cip/Kip CDK "inhibitors" in these processes. We have recently identified the T-loop phosphorylation of CDK4, but not of CDK6, as a determining target for cell cycle control by extracellular factors, indicating that CDK4-activating kinase(s) might have to be reconsidered.

Figure 1

CDK4 regulation: the example of canine thyroid primary cultures. Two distinct mitogenic modes coexist in dog thyrocytes and are differentially associated with differentiation expression. Growth factors (GF) activate CDK4 as in other systems, mainly by inducing cyclin D1 and also p21, which stabilizes the cyclin D1-CDK4 complex in the nucleus. The differentiation-associated cell cycle activation by TSH and cAMP is adjunctive to this basic control. It utilizes cyclin D3 synthesized in response to insulin or IGF-I, and p27. cAMP activates CDK4 by promoting the assembly of the cyclin D3-CDK4 complex, its association with nuclear p27, and finally the activating Thr172-phosphorylation of CDK4 within this complex by an undefined CDK4 activating kinase (CDK4AK). Activation of CDK4 complexed to cyclin D1 or cyclin D3 in these parallel mitogenic stimulations leads to partially different site-specificity of pRb-kinase activity. In this system, TGFβ selectively inhibits the cAMP-dependent activation of cyclin D3-CDK4, not by impairing the formation of this complex, but by preventing its binding to nuclear p27, as well as by inhibiting CDK4 phosphorylation within residual p27-bound cyclin D3-CDK4 complexes. The dog thyrocyte model illustrates the dissociation of the regulated assembly of D-type cyclin-CDK4 complexes from the accumulation of their subunits, the dissociation of the nuclear import of these complexes from their assembly, and the dissociation of the rate-limiting phosphorylation of CDK4 from the formation and nuclear accumulation of the D-type cyclin-CDK4-p27/p21 holoenzyme. Diamond arrowheads represent inductions; the other dashed arrows are activations (+) or inhibitions (-).