Signalling by PI3K isoforms: insights from gene-targeted mice

Vanhaesebroeck, Bart; Ali, Khaled; Bilancio, Antonio; Geering, Barbara; Foukas, Lazaros C.

doi:10.1016/j.tibs.2005.02.008

Cited by 396 publications

(389 citation statements)

References 87 publications

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“…Of these, p110a and p110b are abundant in brain, whereas p110d is restricted to leukocytes. Three genes, PIK3R1, PIK3R2, and PIK3R3, encode the p85a, p85b, and p55g isoforms of the p85 regulatory subunit, respectively (Vanhaesebroeck et al, 2005;Engelman et al, 2006). The PIKR31 gene can also give rise to two smaller regulatory subunits, 50a, and 55a, but less is known about their specific regulatory features.…”

Section: Introductionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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Section: Introductionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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“…Five regulatory class 1A subunits have been defined and they are p85a, p55a, p50a, p85b and p55g. 23 Each of these regulatory subunits has the ability to associate with any of the three catalytic subunits, p110a, p110b and p110d. 23 Upon receptormediated activation, p85/p110 complexes are recruited to 'YINM' motif containing proteins such as DAP10, CD28, CD19, BCAP, Gab and insulin receptor substrate-IRS.…”

Section: Discussionmentioning

confidence: 99%

“…23 Each of these regulatory subunits has the ability to associate with any of the three catalytic subunits, p110a, p110b and p110d. 23 Upon receptormediated activation, p85/p110 complexes are recruited to 'YINM' motif containing proteins such as DAP10, CD28, CD19, BCAP, Gab and insulin receptor substrate-IRS. 47 Membrane-recruited PI3K complexes phosphorylate PIP 2 at D3 position to generate PIP 3 .…”

Section: Discussionmentioning

confidence: 99%

“…22 The p110a and p110b are also ubiquitously expressed, whereas the p110d is predominantly expressed in hematopoietic cells. 23 PI3K binds to lipid substrates in the membrane and generates PIP 2 and PIP 3 that interact with pleckstrin homology (PH) domain containing proteins. Akt, PDK1 and Btk are the major downstream signaling molecules of PI3K signalosomes.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

et al. 2008

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Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85a subunit and its alternatively spliced variants p55a/p50a (collectively termed as p85a À/À ), we defined the role of PI3K in NK cell development and function. p85a À/À mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85a À/À NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85a severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85a À/À NK cells. These results reveal a previously unrecognized role of p85a in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.

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“…Any of the three different Type IA isoforms of p110, called p110a, p110b and p110d, can sustain cell proliferation and survival (Foukas et al, 2010). The physiological role of the a-, b-and d-isoforms is not fully understood, but their differential tissue distribution and the distinct phenotypes produced by their genetic ablation in mice indicate that each isoform has a distinct function (Vanhaesebroeck et al, 2005). Moreover, the b-and d-isoforms of p110 can induce oncogenic transformation when expressed in chicken embryo fibroblasts (Kang et al, 2006), and the activity of the p110a and p110b requires association with GTPbound RAS (Rameh et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is overexpressed in tumors

Fransson

Eriksson

et al. 2011

Oncogene

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The phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, proliferation and survival, and are frequently affected in human cancer. PI3K is composed of a catalytic subunit, p110, and a regulatory subunit, p85. The PI3K catalytic subunit p110d is encoded by PIK3CD and contains p85-and RAS-binding domains, and a kinase domain. Here we present an alternatively spliced PIK3CD transcript encoding a previously unknown protein, p37d, and demonstrate that this protein is expressed in human ovarian and colorectal tumors. p37d retains the p85-binding domain and a fraction of the RAS-binding domain, lacks the catalytic domain, and has a unique carboxyl-terminal region. In contrast to p110d, which stabilizes p85, p37d promoted p85 sequestering. Despite the truncated RAS-binding domain, p37d bound to RAS and we found a strong positive correlation between the protein levels of p37d and RAS. Overexpressing p37d, but not p110d, increased the proliferation and invasive properties of HEK-293 cells and mouse embryonic fibroblasts. Cells overexpressing p37d showed a quicker phosphorylation response of AKT and ERK1/2 following serum stimulation. Ubiquitous expression of human p37d in the fruit fly increased body size, DNA content and phosphorylated ERK1/2 levels. Thus, p37d appears to be a new tumor-specific isoform of p110d with growthpromoting properties.

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Signalling by PI3K isoforms: insights from gene-targeted mice

Cited by 396 publications

References 87 publications

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is overexpressed in tumors

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