Trends in Biochemical Sciences
ReviewTwice upon a time: PI3K's secret double life exposed
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.
References (34)
Signalling through phosphoinositide 3-kinases: the lipids take centre stage
Curr. Opin. Cell Biol.
(1999)PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects
Cell
(2004)Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase γ that is highly expressed in heart and interacts with PDE3B
J. Biol. Chem.
(2006)Identification of a unique co-operative phosphoinositide 3-kinase signaling mechanism regulating integrin αIIbβ3 adhesive function in platelets
J. Biol. Chem.
(2007)A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling
Cell
(2006)Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking
J. Biol. Chem.
(1995)The p85α subunit of phosphatidylinositol 3′-kinase binds to and stimulates the GTPase activity of Rab proteins
J. Biol. Chem.
(2004)The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins
Cell
(1998)Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation
Nature
(2006)Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation
Science
(2000)
The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity
EMBO J.
Phosphatidylinositol 3-kinase activity is required for early endosome fusion
Biochem. J.
PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma
Cancer Res.
Signalling through Class I PI3Ks in mammalian cells
Biochem. Soc. Trans.
Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit
Science
Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ
Cell
The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations
Science
Cited by (53)
In-depth PtdIns(3,4,5)P<inf>3</inf> signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function
2017, Blood AdvancesCitation Excerpt :Despite extensive confirmation of the importance of the class I PI3Ks to platelet function, detailed mechanistic understanding of the events downstream of PI3K activation remains limited. Although class I PI3Ks may have protein kinase activity15 and scaffolding roles,16 they predominantly regulate cell function through the product of their lipid kinase activity, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3].17 PtdIns(3,4,5)P3 is generated by the class I PI3K–catalyzed phosphorylation of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and serves to coordinate the localization and/or activity of a range of binding proteins.17-19
Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow
2017, Journal of Molecular BiologyThe role of class I, II and III PI 3-kinases in platelet production and activation and their implication in thrombosis
2016, Advances in Biological RegulationImbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward
2016, AtherosclerosisCitation Excerpt :The ability of activated PDE3B to promote leptin signaling to STAT3 [568] is particularly intriguing. After hormonal or other stimulations, PDE3B can form several different types of multiprotein complexes [317,571–574]. Members of the 14-3-3 family of proteins are an attractive group of scaffolding molecules for cross-talk of PDE3B with other signaling molecules (the OMIM/HGNC gene symbol for 14-3-3β/α [beta/alpha] is YWHAB and for 14-3-3ζ/δ [zeta/delta] is YWHAZ; seven forms total have been reported in mammals).
Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1
2014, Advances in Biological RegulationCitation Excerpt :Besides this role, class I PI3Ks have also protein scaffolding properties that have been unraveled by comparison of the phenotype of knock-out and knock-in mice models (Ciraolo et al., 2008, Hirsch et al, 2009, Jia et al., 2008, Patrucco et al., 2004). A kinase-independent role of PI3Kγ was first reported in the heart where PI3Kγ negatively regulates cardiomyocytes contractility by forming a complex with phosphodiesterase 3B (Hirsch et al., 2009; Patrucco et al., 2004). Recently, it was shown that p110γ also anchor protein kinase A (PKA) which activates phosphodiesterase 3B and inhibit p110γ, providing a local feedback control of PtdIns(3,4,5)P3 and cAMP signaling events (Ghigo et al., 2012, Perino et al., 2011).