Phosphatidylinositol Kinases (Molecular Biology)

Phosphoinositides serve important functions in controlling the regulation of growth and differentiation in cells, as well as serving as substrates for the generation of inositol trisphosphate, IP3 (see Inositol Lipids and Phosphates). In response to a variety of growth factors and cytokines, phosphatidylinositol (PI) is phosphorylated sequentially, to form the polyphosphoinositide PI-3′,4′,5′-P3 (PIP3). These phosphorylations are catalyzed by the enzyme PI 3′-kinase. The lipid products of this enzyme are not substrates for phospholipases, but instead have direct regulatory properties themselves.

PI 3′-kinase has a number of domains for protein-protein interactions that contribute to its regulation and localization. The enzyme consists of a catalytic (p110) and regulatory (p85) subunit. p85 has two SH2 domains and one SH3 domain, which play a crucial role in regulation of the activity and targeting of the enzyme. Upon growth-factor-receptor activation, p85 is recruited to receptors phosphorylated on tyrosine residues, or their substrates. The occupancy of these SH2 domains in p85 causes activation of the enzyme, while also serving to target it to the plasma membrane, or in some cases to intracellular membranes, where its lipid products can bind to proteins (1).

The generation of 3′ phosphoinositides appears to play an important role in signal transduction. Activation of PI 3′-kinase is necessary for the full expression of a number of tyrosine kinase receptors, including those for insulin, nerve growth factor, and others (1). Activation of the enzyme has been shown to prevent apoptosis in a number of cell types. Moreover, a retrovirus encoding PI 3′-kinase was found to induce hemangiosarcomas in chickens, and mutations in the enzyme were associated with increased life span in Caenorhabditis elegans. Many advances in identifying the role of PI 3′-kinase have come from the use of pharmacological inhibitors, such as wortmannin (1).


The targets of the lipid products of PI 3′-kinase have received a great deal of attention. PI 3′-kinase appears to play a universal role in membrane trafficking, perhaps explaining its wide importance in signal transduction. Cell adhesion molecules can also cause its activation, linking these events to changes in the actin cytoskeleton. Although there have been numerous reports on the essential role that PI 3′-kinase plays in most aspects of signal transduction, most attention has focused on downstream changes in phosphorylation . There have now been a number of protein kinases that are activated after PI 3′-kinase activation. One group belongs to the calcium-independent protein kinase C family members, especially z and q. Additionally, PIP3 can induce a phosphorylation cascade.

This involves the activation of the serine/threonine kinases PDK and Akt, which is also known as protein kinase B (PKB). It is now thought that PIP3 can bind to the pleckstrin homology (PH) domain of these kinases, effectively recruiting them to the plasma membrane or intracellular membranes for activation. While PDK appears to be controlled mainly by targeting, it can phosphorylate and activate Akt, which in turn can phosphorylate a variety of intracellular substrates, including transcription factors, other kinases, proteins controlling apoptosis, and others (1).

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