Review
Twice upon a time: PI3K's secret double life exposed

https://doi.org/10.1016/j.tibs.2009.02.003Get rights and content

Class I phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes involved in signal transduction triggered by growth factors and G-protein-coupled receptors. The catalytic function of PI3Ks is well known to promote a wide variety of biological processes, including proliferation, survival and migration, but a new layer of complexity in the function of PI3Ks has recently emerged, indicating that these proteins function not only as kinases but also as scaffold proteins. Knockout mice that lack PI3K protein expression show a different phenotype from knock-in mice expressing PI3K mutants that have lost their kinase activity, providing evidence for this novel role of PI3Ks. We will discuss such findings, highlighting the crucial scaffold function of PI3Kγ in cAMP homeostasis and PI3Kβ in receptor recycling.

Section snippets

Setting the stage

The enzymatic activity of phosphoinositide 3-kinases (PI3Ks) is essential in eukaryotic cells to regulate many processes, such as cytoskeletal dynamics, transcription, protein synthesis, metabolic responses and membrane trafficking 1, 2, 3, 4. PI3Ks are recruited and activated downstream of tyrosine kinase receptors (RTKs) and G-protein-coupled receptors (GPCRs) and phosphorylate phosphoinositides (PIs) in their D3 position. Three different PI3K classes can be distinguished based on their

Kinase-independent roles of p110γ

p110γ is activated by Gβγ subunits of GPCRs. The biological roles of this class I PI3K have been well characterized in hematopoietic cells, where p110γ activates a downstream signaling pathway essential for the regulation of immunity and inflammation [2]. Accordingly, p110γ-null mice present reduced leukocyte migration towards inflammatory sites, which is phenocopied by mice that express a kinase-dead p110γ (p110γKD/KD) [13]. Furthermore, selective p110γ inhibitors are anti-inflammatory in

Kinase-independent roles of p110β

p110β is ubiquitously expressed, and its kinase activity shows the unique ability among class I PI3Ks to be triggered by both RTKs and GPCRs 21, 22. The p110β catalytic subunit has a fundamental role in mammalian embryonic development, and its absence in mice causes an early embryonic lethal phenotype [23]. Unexpectedly, however, mice expressing a catalytically inactive p110β are born and reach adulthood [21]. This discrepancy between phenotypes caused by the p110β-null and kinase-dead mutants

The TRRAP-ing factor

Where interactors bind p110s and how they trigger the p110 scaffolding function are not yet fully understood. The sequences of p110 that are involved in any protein–protein interactions seem to involve multiple domains. Regions previously thought to be only required for kinase activity (e.g. the PIK domain in substrate selection) are now also considered as preferential sites for the protein binding. In line with this, even the kinase domain could be involved in protein–protein interactions.

Concluding remarks and future perspectives

The differences in physiology between kinase-null mice and kinase-dead mutants have exposed a previously untold story for PI3K, one in which their catalytically active subunits have been found to have an unconventional scaffolding role. This chapter is still relatively new and, as such, is ripe for speculation on its importance to the cell. Therefore, we must limit ourselves in the short term to the basics of discovering more about the who and what of interaction before we can learn the why.

Acknowledgements

This work was supported by the European Union Sixth Framework Programme (FP6) EUGeneHeart project, Fondation Leducq and the Telethon Foundation.

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