Nuclear protein phosphorylation and growth control.

Protein phosphorylation regulates a diverse range of cellular processes. A rapidly growing area of interest in the study of protein phosphorylation is the regulation of cellular growth through phosphorylation of key nuclear proteins. The growing list of such nuclear 'effector' proteins includes proto-oncogene products that function as transcription factors as well as tumour suppressor proteins that may be involved in regulating the onset ofDNA replication. Regulation of the activities of these proteins can occur through phosphorylation and dephosphorylation mechanisms that in turn respond to the timing mechanism of the cell cycle, or directly to extracellular signals transduced to the nucleus by 'cascade events'. In addition, some viral proteins that stimulate cellular growth are also regulated by phosphorylation or are able to influence the phosphorylation of proteins central to growth regulation (Fig. 1). This Review examines the phosphorylation of a selected number of nuclear proteins that are involved in the control of cellular growth and that illustrate the extent ofpresent knowledge about nuclear signal transduction. These proteins include the transcription factors, CREB, Jun, Fos, NFKB, Myc and Myb, four of which are the products of proto-oncogenes (Jun, Fos Myc and Myb); two tumour suppressor proteins, p53 and the product of the retinoblastoma susceptibility gene (pRB); and the simian virus 40 (SV40) large tumour antigen (T antigen) which is a multifunctional viral protein involved in DNA replication, transcription and cellular transformation. The effects of phosphorylation on biochemical activity and biological function are discussed, together with the protein kinases and phosphatases involved and their response to a valiety of growth factors and tumour promoters. Interestingly, several of these proteins are phosphorylated by the same protein kinases, suggesting that signals may co-ordinately target these key proteins. In some cases, there is a relationship between nuclear phosphorylation events and cellular transformation in which oncogene products play a role. Each protein is multiply phosphorylated and in some cases phosphorylation at a particular site occurs in response to different signals. Finally, some proteins respond directly to external stimuli while others are phosphorylated temporally in response to the timing mechanism of the cell cycle. Taken together, these examples give an overview of the role of phosphorylation of nuclear proteins in growth control.