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Journal ArticleDOI

The emerging mechanisms of isoform-specific PI3K signalling

01 May 2010-Nature Reviews Molecular Cell Biology (Nature Publishing Group)-Vol. 11, Iss: 5, pp 329-341
TL;DR: A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.
Abstract: Phosphoinositide 3-kinases (PI3Ks) function early in intracellular signal transduction pathways and affect many biological functions. A further level of complexity derives from the existence of eight PI3K isoforms, which are divided into class I, class II and class III PI3Ks. PI3K signalling has been implicated in metabolic control, immunity, angiogenesis and cardiovascular homeostasis, and is one of the most frequently deregulated pathways in cancer. PI3K inhibitors have recently entered clinical trials in oncology. A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.
Citations
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Journal ArticleDOI
20 Apr 2017-Cell
TL;DR: Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.

2,187 citations


Cites background from "The emerging mechanisms of isoform-..."

  • ...effector of PI3K signaling and influences most phenotypes associated with PI3K pathway activation, it is worth noting that many other downstream effectors of PI3K exist that are activated in parallel to AKT and contribute to the subsequent cellular response (Vanhaesebroeck et al., 2010)....

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  • ...Class I PI3Ks predominantly phosphorylate PI4,5P2, thereby producing PIP3 (Vanhaesebroeck et al., 2010), whereas the synthesis of PI3,4P2 typically follows, perhaps resulting from the action of the 50-phosphatase SH2-domain-containing inositol 50-phosphatase (SHIP) on PIP3 (Franke et al., 1997;…...

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  • ...…studied effector of PI3K signaling and influences most phenotypes associated with PI3K pathway activation, it is worth noting that many other downstream effectors of PI3K exist that are activated in parallel to AKT and contribute to the subsequent cellular response (Vanhaesebroeck et al., 2010)....

    [...]

  • ...Class I PI3Ks predominantly phosphorylate PI4,5P2, thereby producing PIP3 (Vanhaesebroeck et al., 2010), whereas the synthesis of PI3,4P2 typically follows, perhaps resulting from the action of the 50-phosphatase SH2-domain-containing inositol 50-phosphatase (SHIP) on PIP3 (Franke et al....

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Journal ArticleDOI
TL;DR: The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus, which will undoubtedly inform the rational design of novel therapies.
Abstract: Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Unravelling its enzymatic activities, its signalling partners, and the molecular mechanisms involved in the multiple levels of PTEN regulation will aid the design of novel PTEN-based therapeutic interventions in cancer The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer By suppressing the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein–protein interactions, are all altered in cancer The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies

1,593 citations

Journal ArticleDOI
10 Aug 2017-Cell
TL;DR: A perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions is provided, two topics closely intertwined with cancer biology.

1,461 citations


Cites background from "The emerging mechanisms of isoform-..."

  • ...Generation of mice with deletion or mutation of PI3K genes has been instrumental in delineating the unique and redundant functions of PI3K isoforms in mammalian cells and tissues (Okkenhaug, 2013; Vanhaesebroeck et al., 2010)....

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Journal ArticleDOI
TL;DR: Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
Abstract: The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

1,396 citations

Journal ArticleDOI
TL;DR: This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.
Abstract: Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

1,239 citations


Cites background from "The emerging mechanisms of isoform-..."

  • ...These enzymes also exist in three forms in mammalian cells: PI3KC2 , PI3KC2 , and PI3KC2 (1347, 1610)....

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  • ...PI3KC3,(Vps34), PI3KC2A 4....

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References
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Journal ArticleDOI
23 Oct 2008-Nature
TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

6,761 citations

Journal ArticleDOI
11 Jan 2008-Cell
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

6,301 citations

Journal ArticleDOI
26 Sep 2008-Science
TL;DR: Recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival.
Abstract: Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

5,250 citations


"The emerging mechanisms of isoform-..." refers background in this paper

  • ..., as well as large-scale sequencing efforts of cancer genome...

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Journal ArticleDOI
23 Apr 2004-Science
TL;DR: To determine if PI3Ks are genetically altered in tumorigenesis, they were sequenced in human for the first time and the results allowed us to assess the importance of phosphatidylinositol 3-kinases in neoplasia.
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways important for neoplasia, including cell proliferation, adhesion, survival, and motility ([ 1 ][1]–[ 3 ][2]). To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in human

3,396 citations


"The emerging mechanisms of isoform-..." refers background in this paper

  • ...sequenced the predicted kinase domains of the eight PI3K and eight PI3K-like genes in cancer and found tumour-specific (somatic) mutations only in PIK3CA , the gene encoding p110...

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PatentDOI
08 Oct 2008-Science
TL;DR: Based on analysis of exons representing 20,857 transcripts from 18,191 genes, the authors concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency.
Abstract: Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalogue the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

2,742 citations