Phosphatidylinositol-3-kinase can generate other important signalling molecules. Over the last decade it has become apparent that, not only do many cells contain phosphatidylinositol-3-kinases but, on stimulation, such cells increase their concentration of 3-phosphorylated lipids markedly. (Normally the levels of such lipids are very low.) Two major iso-forms of phosphatidylinositol-3-kinase have been found and activation connected to such events as stimulation of mitogenesis, triggering of differentiation and insulin responses (Table 7.11). Some forms of protein kinase C are stimulated by phos-phatidylinositol-3,4,5-trisphosphate and this lipid can also activate serine/threonine kinases Akt (named after their similarity to the transforming oncogene of the retrovirus Akt 8).
Table 7.11 Cellular functions regulated by phosphatidylinositol-3-kinases
Cellular proliferation Vesicular trafficking Cytoskeletal structure Cellular morphology Glucose utilisation Protein biosynthesis Lipid metabolism
The Akt/protein kinase B family of kinases contain a pleckstrin homology (PH) domain that can bind 3-phosphorylated inositol phospholipids. This leads to their activation via phosphorylation of the activation loop. In fact, the PH domain itself seems to inhibit the phosphorylation of Akt kinases and it is only after the 3-phosphorylated inositol lipids have bound that phosphorylation (at the cell membrane) occurs.
Phosphatidylinositol-3-kinase has other important roles. For example, it can activate MAP kinase (via its protein kinase activity). MAP kinase is part of another important cell-signalling pathway and this activity of the 3-kinase provides a connection between two different signalling pathways. Such interactions are known as 'cross-talk'. The protein kinase activity of 3-kinases also has serine residues of the catalytic and regulatory subunits of itself as major substrates. Such autophosphorylation regulates 3-kinase activity.
Just as metabolism of phosphatidylinositol-4,5-bisphosphate was associated with nuclear membranes as well as the plasma membrane, 3-kinase activity also has a dual localization. Various agents (e.g. insulin, vitamin D) have been reported to increase translocation of the 3-kinase to the nucleus. Activity of the 3-kinase to produce phosphatidyl-inositol-3,4,5-irisphosphate in the nucleus then leads to activation of protein kinase C or phospholipase C-y and, hence, to signalling actions.
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