Involvement of G proteins, cytoplasmic calcium, phospholipases, phospholipid-derived second messengers, and protein kinases in signal transduction from mitogenic cell surface receptors.

Some putative mitogenic signal transduction mechanisms involving G proteins, calcium, phospholipases, and protein kinases have been discussed. Several elements in this signal transduction scheme are not yet well understood and require further experimental investigation. With regard to the heptahelix receptors, exactly how do they activate PLA2? Is PLA2 activation linked to mitogenic pathways? Is this via stimulation of protein kinase C or perhaps another mechanism? How do heptahelix receptors activate tyrosine phosphorylation, and is it important in their ability to stimulate cell growth? With regard to the various phospholipases that are thought to be regulated by receptor-mediated stimuli, only PI-PLC beta and PI-PLC gamma are well characterized. PLA2, PC-PLD, and PC-PLC require further study in regard to determination of molecular structure and elucidation of mechanisms of phospholipase activation (e.g., what are the molecular mechanisms whereby tyrosine kinases and Ras affect PC-PLC?). The protein kinase C dependent and protein kinase C independent mechanisms that enable mitogenic stimuli to activate the Erk/MAP kinase are enigmatic at this time. How Raf-1 activates SRE-containing gene promoters (such as the fos promoter) is also not known. However, given the current rapid rate of progress in this field, it is likely that a much more complete understanding of the mitogenic signal transduction process will soon be obtained.