Cytoskeletal events during calcium- or EGF-induced initiation of DNA synthesis in cultured cells. Role of protein phosphorylation and clues in the transformation process.

The possible relationship between cytoskeletal events and growth regulation in response to stimulation by calcium and by growth factors such as EGF can be summarized as follows: An elaborate interaction exists between calcium and serum growth factors, such as EGF, in the initiation of DNA synthesis in quiescent cells. This implies that many processes between the external signals delivered at the cell surface and the sequential intracellular events that lead to chromosomal replication, and ultimately to cell division, must be coordinated in a reproducible manner. It is now apparent that because of its possible role as a dynamic integrator of the cytoplasm, the cytoskeleton could represent the coordinator of the events that lead to replication. Calcium (with its intracellular acceptor, calmodulin) and cAMP (which can act by opposing mechanisms) are extensively involved in the control of the integrity of the cytoskeleton. Distinct protein kinases are activated by calcium/calmodulin, EGF, and cAMP as aspects of the prereplicative response, and many of the substrates for phosphorylation are cytoskeletal proteins. The emerging picture seems to include a direct involvement of these protein kinases in the cascade of regulatory events that leads to the initiation of DNA synthesis. Thus, the cytoskeleton has a direct role in the transmission of proliferative signals from external receptor sites to the nucleus. A means by which neoplastic cells can bypass the normal regulatory pathways is proposed in the light of recent data showing that the product of oncogenes are protein kinases or proteins that intimately interact with cellular protein kinases.