PP1 and PP2A phosphatases--cooperating partners in modulating retinoblastoma protein activation.
The retinoblastoma/pocket protein family is one of the master regulators of the eukaryotic cell cycle. It includes the retinoblastoma protein (Rb) and the related p107 and p130 proteins. The importance of the Rb pathway for homeostasis and tumour suppression is evident from the fact that inactivating mutations in Rb are frequently associated with many cancers. Rbs regulate the cell cycle by controlling the activity of the E2F family of transcription factors. The activity of Rb proteins themselves is modulated by their phosphorylation status at several Ser/Thr residues: phosphorylation by cyclin-dependent kinases inactivates Rb proteins and positively influences the transcription of genes necessary for cell cycle progression. Although the mechanisms of cyclin-dependent kinase-mediated inactivation of Rb proteins are understood in great detail, our knowledge of the process that counteracts Rb phosphorylation is still quite limited. The present review focuses on the Ser/Thr phosphatases that are responsible for the dephosphorylation and thus activation of Rb proteins. Two major scenarios are considered: (a) when pocket proteins are dephosphorylated during regular cell cycle progression and (b) when rapid dephosphorylation is dictated by external stress or growth inhibitory conditions, such as oxidative stress, UV radiation or other DNA-damaging stimuli, and cell differentiation factors. It transpires that protein phosphatase 1 and protein phosphatase 2A can efficiently modulate pocket protein activity in a highly context-dependent manner and both are tightly regulated by the presence of different regulatory subunits or interacting proteins.
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. victoria.kolupaeva@nyumc.org
Victoria
V
Kolupaeva
Veerle
V
Janssens
D002453:Cell Cycle; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism
D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2