A novel view on the mechanisms of action of insulin and other insulin superfamily peptides: involvement of adenylyl cyclase signaling system.
A new signaling mechanism common to mammalian insulin, insulin-like growth factor I, relaxin and mollusc insulin-like peptide, and involving receptor-tyrosine kinase==>G(i) protein (betagamma)==>phosphatidylinositol-3-kinase==>protein kinase Czeta==>adenylyl cyclase==>protein kinase A was discovered in the muscles and some other tissues of vertebrates and invertebrates. The authors' data were used to reconsider the problem of participation of the adenylyl cyclase-cAMP system in the regulatory effects of insulin superfamily peptides. A hypothesis has been put forward according to which the adenylyl cyclase signaling mechanism producing cAMP has a triple co-ordinating role in the regulatory action of insulin superfamily peptides on the main cell processes, inducing the mitogenic and antiapoptotic effects and inhibitory influence on some metabolic effects of the peptides. It is suggested that cAMP is a key regulator responsible for choosing the transduction pathway by concerted launching of one (proliferative) program and switching off (suppression) of two others, which lead to cell death and to the predomination of anabolic processes in a cell. The original data obtained give grounds to conclude that the adenylyl cyclase signaling system is a mechanism of signal transduction not only of hormones with serpentine receptors, but also of those with receptors of the tyrosine kinase type (insulin superfamily peptides and some growth factors).
Pertseva
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MN
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez av. 44, 194223 St. Petersburg, Russia. sveta@iephb.ru
Shpakov
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AO
Plesneva
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SA
Kuznetsova
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LA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D009132:Muscles / Q000201:enzymology; D010455:Peptides / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D010455:Peptides; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000262:Adenylyl Cyclases