Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation (original) (raw)
Related papers
Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism
EMBO Molecular Medicine, 2013
The insulin/insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110a, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110a impair insulin signalling and cause insulin resistance, inducing a prediabetic state. It remains unknown if long-term p110a inactivation induces further metabolic deterioration over time, leading to overt unsustainable pathology. Surprisingly, we find that chronic p110a partial inactivation in mice protects from age-related reduction in insulin sensitivity, glucose tolerance and fat accumulation, and extends the lifespan of male mice. This beneficial effect of p110a inactivation derives in part from a suppressed down-regulation of insulin receptor substrate (IRS) protein levels induced by age-related hyperinsulinemia, and correlates with enhanced insulin-induced Akt signalling in aged p110a-deficient mice. This temporal metabolic plasticity upon p110a inactivation indicates that prolonged PI3K inhibition, as intended in human cancer treatment, might not negatively impact on organismal metabolism.
Dominant negative effect of the truncated p110 subunit of phosphatidylinositol-3 kinase
IUBMB Life, 1996
Effects of p110, the catalytic subunit of PI-3 kinase, on induction of TPA response element-driven promoter by EGF was examined. The induction was enhanced by co-expression of the wild type p110. The truncated p110 mutants containing the binding site for p85 but missing the catalytic activity repressed the induction. A mutant with no binding activity to p85 did not show this effect. These results suggest that PI-3 kinase is involved in signal transduction of EGF and that the truncated p110s capable of binding to p85 serves as a dominant negative reagent for PI-3 kinase.
Science Signaling, 2008
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB K805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding (G protein)-coupled receptors as well as to sustain long term insulin signaling. In addition, PIK3CB K805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential new avenues for therapeutic intervention.
Role of phosphoinositide 3-OH kinase p110β in skeletal myogenesis
Phosphoinositide 3-OH kinase (PI3K) regulates a number of developmental and physiologic processes in skeletal muscle; however, the contributions of individual PI3K p110 catalytic subunits to these processes are not well defined. To address this question, we investigated the role of the 110 kDa PI3K catalytic subunit β (p110β) in myogenesis and metabolism. In C2C12 cells, pharmacological inhibition of p110β delayed differentiation. We next generated mice with conditional deletion of p110β in skeletal muscle (p110β-mKO). While young p110β-mKO mice possessed less quadriceps mass and exhibited less strength than control littermates, no differences in muscle mass or strength were observed between genotypes in old mice. However, old p110β-mKO mice were less glucose tolerant than old control mice. Overexpression of p110β accelerated differentiation in C2C12 cells and primary human myoblasts through an Akt-dependent mechanism, while expression of kinase-inactive p110β had the opposite effect. p110β overexpression was unable to promote myoblast differentiation under conditions of p110α inhibition, but expression of p110α was able to promote differentiation under conditions of p110β inhibition. These findings reveal a role for p110β during myogenesis, and demonstrate that long-term reduction of skeletal muscle p110β impairs whole-body glucose tolerance without affecting skeletal muscle size or strength in old mice.
Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
Open Life Sciences, 2015
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110α catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110α (myr-p110α). The myristoylated version of p110α brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110α catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110α in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110α heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo a...
Proceedings of the National Academy of Sciences, 2008
The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110␣, p110, and p110␦) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110␣ and p110␦ to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110␥ class IB PI3K lack SH2 domains and instead couple p110␥ to G protein-coupled receptors (GPCRs). Here, we show, using smallmolecule inhibitors with selectivity for p110 and cells derived from a p110-deficient mouse line, that p110 is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110 and p110␥ contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110 but not p110␥, p110 mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110␥ in these cells reduced the contribution of p110 to GPCR signaling. Taken together, these data show that p110 and p110␥ can couple redundantly to the same GPCR agonists. p110, which shows a much broader tissue distribution than the leukocyterestricted p110␥, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110␥ expression is low or absent.
Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits?
Biochemical Society Transactions, 2007
Class IA PI3Ks (phosphoinositide 3-kinases) consist of a p110 catalytic subunit bound to one of five regulatory subunits, known as p85s. Under unstimulated conditions, p85 stabilizes the labile p110 protein, while inhibiting its catalytic activity. Recruitment of the p85-p110 complex to receptors and adaptor proteins via the p85 SH2 (Src homology 2) domains alleviates this inhibition, leading to PI3K activation and production of PIP 3 (phosphatidylinositol 3,4,5-trisphosphate). Four independent p85 KO (knockout) mouse lines have been generated. Remarkably, PI3K signalling in insulin-sensitive tissues of these mice is increased. The existence of p110-free p85 in insulin-responsive cells has been invoked to explain this observation. Such a monomeric p85 would compete with heterodimeric p85-p110 for pTyr (phosphotyrosine) recruitment, and thus repress PI3K activity. Reduction in the pool of p110-free p85 in p85 KO mice was thought to allow recruitment of functional heterodimeric p85-p110, leading to increased PI3K activity. However, recent results indicate that monomeric p85, like p110, is unstable in cells. Moreover, overexpressed free p85 does not necessarily compete with heterodimeric p85-p110 for receptor binding. Using a variety of approaches, we have observed a 1:1 ratio between the p85 and p110 subunits in murine cell lines and primary tissues. Alternative models to explain the increase in PI3K signalling in insulin-responsive cells of p85 KO mice, based on possible effects of p85 deletion on phosphatases acting on PIP 3 , are discussed.
Proceedings of The National Academy of Sciences, 2008
The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110␣, p110, and p110␦) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110␣ and p110␦ to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110␥ class IB PI3K lack SH2 domains and instead couple p110␥ to G protein-coupled receptors (GPCRs). Here, we show, using smallmolecule inhibitors with selectivity for p110 and cells derived from a p110-deficient mouse line, that p110 is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110 and p110␥ contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110 but not p110␥, p110 mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110␥ in these cells reduced the contribution of p110 to GPCR signaling. Taken together, these data show that p110 and p110␥ can couple redundantly to the same GPCR agonists. p110, which shows a much broader tissue distribution than the leukocyterestricted p110␥, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110␥ expression is low or absent.
Regulation of p110δ PI 3-Kinase Gene Expression
PLoS ONE, 2009
Background: Despite an intense interest in the biological functions of the phosphoinositide 3-kinase (PI3K) signalling enzymes, little is known about the regulation of PI3K gene expression. This also applies to the leukocyte-enriched p110d catalytic subunit of PI3K, an enzyme that has attracted widespread interest because of its role in immunity and allergy.