Regulation of protein phosphorylation by insulin and insulin-like growth factors in cultured fetal neurons.
The pathways depicted in Figure 1 summarize the data discussed in this article. In neurons, the binding of insulin and IGF-I to their respective receptors triggers autophosphorylation of the receptor beta-subunits. IGF-II binds to both neuronal insulin and IGF-I receptors and can stimulate autophosphorylation of either receptor type. In addition to enhancing insulin and IGF-I receptor autophosphorylation, all 3 peptides stimulate the tyrosine phosphorylation of a 70 kDa protein with a similar time course and dose response to receptor phosphorylation. The identity of pp70 is unknown, although the close temporal relationship between pp70 phosphorylation and neurite outgrowth suggests a potential role for this protein. Subsequent to these very early events, two neuronal serine kinases are activated by insulin. One has S6 kinase activity and may represent either the pp90rsk or pp70 class of S6 kinases. Since S6 kinases are activated by direct phosphorylation rather than by second messengers, it is likely that a neuronal S6 kinase kinase exists. The activation of S6 kinase is likely to mediate insulin's effects on neuronal protein synthesis or other growth-related processes. The second serine kinase that is activated by insulin is PKC epsilon. This enzyme is largely restricted to the nervous system, so this signalling pathway may be neuronal-specific. The mechanism of activation of PKC epsilon is unknown, although preliminary data suggests that enhanced phosphorylation of the enzyme is involved. Studies are currently underway to investigate the potential role of diacylglycerol, a potential second messenger generated from either phosphotidylinositol or phosphotidylcholine hydrolysis, in the activation of PKC epsilon by insulin.
Heidenreich
K A
KA
Department of Medicine, University of California, San Diego, La Jolla 92093.
Toledo
S P
SP
Kenner
K A
KA
D002478:Cells, Cultured; D005326:Fetal Proteins / Q000378:metabolism*; D007328:Insulin / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017451:Receptors, Somatomedin; D013002:Somatomedins / Q000502:physiology*
D005326:Fetal Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D013002:Somatomedins; D011972:Receptor, Insulin