Fig. 1: The effect of CDK regulators and the relevant signalling pathways which impinge on them.

a CDK regulation and the subsequent effect on Rb repression of cell cycle gene expression: CDK activity is directly regulated by various activating Cyclins, Cdc25 phosphatases, and CDK activating kinase (CAK), or by repressive INK4 and Cip/Kip CDK inhibitors (CKIs) [21, 22], and Wee1 and Myt1 kinases [20]. Active Cyclin-CDK complexes promote expression of cell cycle master transcription factor E2F through hyperphosphorylation of retinoblastoma protein (Rb) [20, 27, 165]. b Multiple signalling pathways converge on CDK activity to determine proliferation/quiescence decisions. The proliferative and quiescent signalling pathways shown here modulate CDK activity through activating Cyclins or repressive CKIs, (outlined in (a)). Though the pathways here are simplified and not exhaustive of all involved, they depict those most relevant to this review and to CDK control. The ERK/p38 signalling ratio is highlighted as it is a key determinant of quiescence [30, 154, 166]. Both extracellular signal regulated kinase (ERK) and p38 are MAPK family proteins which, when activated by MAPK phosphorylation cascades, will translocate into the nucleus to regulate cellular processes and modify gene expression [167, 168]. ERK1/2 transmits growth and mitogenic signals from RAS/RAF/MEK phosphorylation cascades and stabilisation of growth factor response transcription factor families FOS, JUN and MYC which then drive cell cycle gene expression, including Cyclins^18,26–28. Conversely, extracellular stress and inflammatory cytokines trigger phosphorylation cascades via MKK3/6 to activate p38, which reduces proliferation and promotes survival by increasing the expression of CKIs [167]. The TGFb and BMP pathway is a large pleiotropic signalling network that plays a key role in quiescence. Here we show only the relevant and simplified aspects of canonical and non-canonical pathways. Canonical TGFb signalling occurs when ligand-receptor binding causes phosphorylation of Smad proteins which translocate into the nucleus to join co-activator FoxO proteins. This active complex couples with transcription factors, such as p53, to increase expression of CKIs p15, p21 and p27. Non-canonical TGFb signalling describes when ligand-receptor binding stimulates MAPK cascades which regulate transcription via p38 mechanisms to modulate CDK activity [49, 50].