Lipids (DAG, IP3) and Ca ++ mediated signal transduction.
Some external signals have been found to stimulate the turnover of a membrane lipid and change the intracellular concentration of Ca++
. In this connection, the metabolism of phosphatidylinositides
(Pls) has been shown toplay an important role in the regulation of cell growth. It was also shown that increased PI metabolism is a reflection of signal transduction across the cell membrane. In 1980s, the activation of receptors could be linked to the rapid hydrolysis of PIs and mobilization of Ca++
in many tissues in response to a variety of external stimuli. This hydrolysis of a PI (phosphatidylinositol 4,5 bisphosphate = PIP2)
utilizes an amplifier enzyme, the Pi-specific phospholipase
and produces various messenger molecules, of which the following three 'lipid second messengers' have been documented : (i) 1, 2-diacylglycerol
(ii) inositol 1, 4, 5,-triphosphate
(Ins 1, 4, 5, - P3
)and (iii) archidonic acid.
Hydrolysis of PIP2
, upon binding of extracellular ligands to cell surface receptors, is also coupled to G-protein activation. Activated G-protein modulates PLC, which in turn hydrolysis PIP2
into DAG and IP3
. Although, the signal transduction utilizing these lipid messengers has been shown to be complex, it has been shown that DAG serves as a co-factor and together with Ca++
activates protein kinase C
(PKC). During this process, DAG itself is metabolized to archidonic acid, a precursor of other mediators. (PKC plays a central role in the transduction of extracellular signals into a cellular response). On the other hand, IP3
promotes the release of Ca++
into the cytoplasm through binding to a specific receptor on the surface of endoplasmic reticulum and/or other intracellular vesicles that store Ca++
This interaction induced a conformational change in proteins specific to Ca++
channel and allows Ca++
ions to exit from intracellular storage sites into the cytoplasm. This calcium influx following stimulation of the PI signal pathway is a widespread and physiologically most important phenomenon. Ca+ +
in the cytoplasm has several roles to play in the cellular regulation, including activation of PKC by DAG. In view of the role of IP3 as a 'second messenger' in operating Ca+ +
channels as above, these Ca++
channels have been described, in the past, as SMOCs (second messenger operated calcium channels). However, since the role of 'second messengers' is not fully established, the usage of the term SMOC has recently been questioned.
Ras mediated signal transduction for cell division.
It has been known for some years, that signals received at the cell surface are transmitted via activated tyrosine kinase (associated with the receptor) on the cell surface, through serine/threonine kinase in the cytoplasm, to the transcription factor in the nucleus (among other targets). One such signal transduction pathway, discovered fully in 1992-1993, involves a flow of signal via Ras (product of proto-oncogene c-ras
;consult Genetics of Cancer : Proto-oncogenes, Oncogenes and Tumour Suppressor Genes
for proto-oncogenes) to Raf-1 kinase (product of another oncogene, raf-1
thence of MAPkinases and pp90rsk
and finally onto nuclear proto-oncogene products like c-Fos, c-Jun, etc. (MAP = mitogen activated protein; pp90rsk
= ribosomal S6 kinase).