Phosphoinositides and cell proliferation

Certain growth factors act by stimulating the hydrolysis of inositol lipids to yield putative second messengers such as diacylglycerol (DG) and inositol trisphosphate (IP3). One function of the former is to stimulate C-kinase, which may act by switching on a sodium/hydrogen exchanger to induce the increase in pH that appears to have a permissive effect on DNA synthesis. Studies on Swiss 3T3 cells have revealed that growth factors stimulate an increase in two separate isomers of IP3. In addition to inositol 1,4,5-trisphosphate there was a large increase in inositol 1,3,4-trisphosphate. While the former functions to elevate intracellular calcium, which has been implicated in the control of growth of many different cell types, the function of the latter is unknown. Since the 1,3,4 isomer turns over very slowly, it may control long-term events and thus could play a role in cell growth. There are other growth factors such as insulin and epidermal growth factor (EGF), which apparently do not work through the inositol lipids but they may initiate ionic events similar to those just described for calcium-mobilizing receptors. The bifurcating signal pathway based on IP3/Ca2+ and DG/C-kinase provides an interesting framework within which to consider the mode of action of oncogenes.