scholarly journals The class IA phosphatidylinositol 3-kinase p110-β subunit is a positive regulator of autophagy

2010 ◽  
Vol 191 (4) ◽  
pp. 827-843 ◽  
Author(s):  
Zhixun Dou ◽  
Mohar Chattopadhyay ◽  
Ji-An Pan ◽  
Jennifer L. Guerriero ◽  
Ya-Ping Jiang ◽  
...  
Keyword(s):  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Cell Renewal ◽  
Phosphatidylinositol 3 Kinase ◽  
Positive Regulator ◽  
Evolutionarily Conserved ◽  
Kinase Cascade ◽  
Tor Kinase ◽  
Multicellular Organisms ◽  
Phosphatidylinositol 3

Autophagy is an evolutionarily conserved cell renewal process that depends on phosphatidylinositol 3-phosphate (PtdIns(3)P). In metazoans, autophagy is inhibited by PtdIns(3,4,5)P3, the product of class IA PI3Ks, which mediates the activation of the Akt–TOR kinase cascade. However, the precise function of class IA PI3Ks in autophagy remains undetermined. Class IA PI3Ks are heterodimeric proteins consisting of an 85-kD regulatory subunit and a 110-kD catalytic subunit. Here we show that the class IA p110-β catalytic subunit is a positive regulator of autophagy. Genetic deletion of p110-β results in impaired autophagy in mouse embryonic fibroblasts, liver, and heart. p110-β does not promote autophagy by affecting the Akt–TOR pathway. Rather, it associates with the autophagy-promoting Vps34–Vps15–Beclin 1–Atg14L complex and facilitates the generation of cellular PtdIns(3)P. Our results unveil a previously unknown function for p110-β as a positive regulator of autophagy in multicellular organisms.

scholarly journals Regulation of the p85/p110 Phosphatidylinositol 3′-Kinase: Stabilization and Inhibition of the p110α Catalytic Subunit by the p85 Regulatory Subunit

1998 ◽  
Vol 18 (3) ◽  
pp. 1379-1387 ◽  
Author(s):  
Jinghua Yu ◽  
Yitao Zhang ◽  
James McIlroy ◽  
Tamara Rordorf-Nikolic ◽  
George A. Orr ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Kinase Activity ◽  
Thermal Inactivation ◽  
Insect Cells ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Lipid Kinase ◽  
Phosphatidylinositol 3

ABSTRACT We propose a novel model for the regulation of the p85/p110α phosphatidylinositol 3′-kinase. In insect cells, the p110α catalytic subunit is active as a monomer but its activity is decreased by coexpression with the p85 regulatory subunit. Similarly, the lipid kinase activity of recombinant glutathione S-transferase (GST)-p110α is reduced by 65 to 85% upon in vitro reconstitution with p85. Incubation of p110α/p85 dimers with phosphotyrosyl peptides restored activity, but only to the level of monomeric p110α. These data show that the binding of phosphoproteins to the SH2 domains of p85 activates the p85/p110α dimers by inducing a transition from an inhibited to a disinhibited state. In contrast, monomeric p110 had little activity in HEK 293T cells, and its activity was increased 15- to 20-fold by coexpression with p85. However, this apparent requirement for p85 was eliminated by the addition of a bulky tag to the N terminus of p110α or by the growth of the HEK 293T cells at 30°C. These nonspecific interventions mimicked the effects of p85 on p110α, suggesting that the regulatory subunit acts by stabilizing the overall conformation of the catalytic subunit rather than by inducing a specific activated conformation. This stabilization was directly demonstrated in metabolically labeled HEK 293T cells, in which p85 increased the half-life of p110. Furthermore, p85 protected p110 from thermal inactivation in vitro. Importantly, when we examined the effect of p85 on GST-p110α in mammalian cells at 30°C, culture conditions that stabilize the catalytic subunit and that are similar to the conditions used for insect cells, we found that p85 inhibited p110α. Thus, we have experimentally distinguished two effects of p85 on p110α: conformational stabilization of the catalytic subunit and inhibition of its lipid kinase activity. Our data reconcile the apparent conflict between previous studies of insect versus mammalian cells and show that p110α is both stabilized and inhibited by dimerization with p85.

scholarly journals Activation of Phosphatidylinositol 3-Kinase in Response to Interleukin-1 Leads to Phosphorylation and Activation of the NF-κB p65/RelA Subunit

1999 ◽  
Vol 19 (7) ◽  
pp. 4798-4805 ◽  
Author(s):  
Nywana Sizemore ◽  
Stewart Leung ◽  
George R. Stark
Keyword(s):  
Nuclear Translocation ◽  
Interleukin 1 ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Transactivation Domain ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Phosphatidylinositol 3

ABSTRACT The work of Reddy et al. (S. A. Reddy, J. A. Huang, and W. S. Liao, J. Biol. Chem. 272:29167–29173, 1997) reveals that phosphatidylinositol 3-kinase (PI3K) plays a role in transducing a signal from the occupied interleukin-1 (IL-1) receptor to nuclear factor κB (NF-κB), but the underlying mechanism remains to be determined. We have found that IL-1 stimulates interaction of the IL-1 receptor accessory protein with the p85 regulatory subunit of PI3K, leading to the activation of the p110 catalytic subunit. Specific PI3K inhibitors strongly inhibit both PI3K activation and NF-κB-dependent gene expression but have no effect on the IL-1-stimulated degradation of IκBα, the nuclear translocation of NF-κB, or the ability of NF-κB to bind to DNA. In contrast, PI3K inhibitors block the IL-1-stimulated phosphorylation of NF-κB itself, especially the p65/RelA subunit. Furthermore, by using a fusion protein containing the p65/RelA transactivation domain, we found that overexpression of the p110 catalytic subunit of PI3K induces p65/RelA-mediated transactivation and that the specific PI3K inhibitor LY294,002 represses this process. Additionally, the expression of a constitutively activated form of either p110 or the PI3K-activated protein kinase Akt also induces p65/RelA-mediated transactivation. Therefore, IL-1 stimulates the PI3K-dependent phosphorylation and transactivation of NF-κB, a process quite distinct from the liberation of NF-κB from its cytoplasmic inhibitor IκB.

Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease

Gerontology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Timothy A. Donlon ◽  
Randi Chen ◽  
Kamal H. Masaki ◽  
Bradley J. Willcox ◽  
Brian J. Morris
Keyword(s):  
Cardiovascular Disease ◽  
Life Span ◽  
Mortality Risk ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Survival Curves ◽  
Genotypic Effect ◽  
Hazard Ratios ◽  
Phosphatidylinositol 3

<b><i>Introduction:</i></b> Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (<i>PIK3R1</i>) is associated with longevity. <b><i>Objective:</i></b> The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. <b><i>Methods:</i></b> We performed a longitudinal study of longevity-associated <i>PIK3R1</i> single-nucleotide polymorphism <i>rs7709243</i> genotype by CVD status in 3,584 elderly American men of Japanese ancestry. <b><i>Results:</i></b> At baseline (1991–1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (<i>p</i> = 1.7 × 10<sup>−5</sup>). However, survival curves of CVD subjects differed according to <i>PIK3R1</i> genotype. Those with longevity-associated <i>PIK3R1 TT</i>/<i>CC</i> had survival curves similar to those of subjects without a CVD (<i>p</i> = 0.11 for <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.054 for <i>TC</i>), whereas survival curves for CVD subjects with the <i>CT</i> genotype were significantly attenuated compared with survival curves of subjects without a CVD (<i>p</i> = 0.0000012 compared with <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.0000028 compared with <i>TC</i>). Men without CVD showed no association of longevity-associated genotype with life span (<i>p</i> = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14–1.39; <i>p</i> = 0.0000043) for <i>CT</i> subject with CVD and 1.07 (95% CI 0.99–1.17; <i>p</i> = 0.097) for <i>CC</i>/<i>TT</i> subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. <b><i>Conclusion:</i></b> Our study provides novel insights into the basis for <i>PIK3R1</i> as a longevity gene. We suggest that the <i>PIK3R1</i> longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

scholarly journals Phosphatidylinositol 3-kinase: Structure and expression of the 110 kd catalytic subunit

Cell ◽  
1992 ◽  
Vol 70 (3) ◽  
pp. 419-429 ◽  
Author(s):  
Ian D. Hiles ◽  
Masayuki Otsu ◽  
Stefano Volinia ◽  
Michael J. Fry ◽  
Ivan Gout ◽  
...  
Keyword(s):  
Catalytic Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Kinase Structure ◽  
Phosphatidylinositol 3

scholarly journals Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769552 ◽  
Author(s):  
Ebubekir Dirican ◽  
Mustafa Akkiprik
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3

Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%–30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.

scholarly journals Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

2006 ◽  
Vol 282 (7) ◽  
pp. 4983-4993 ◽  
Author(s):  
Nandini Ghosh-Choudhury ◽  
Chandi Charan Mandal ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Dominant Negative ◽  
Bone Morphogenetic Protein 2 ◽  
Regulatory Subunit ◽  
Type I ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Morphogenetic Protein ◽  
Phosphatidylinositol 3

Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.

scholarly journals Roles of 1-phosphatidylinositol 3-kinase and ras in regulating translocation of GLUT4 in transfected rat adipose cells.

1995 ◽  
Vol 15 (10) ◽  
pp. 5403-5411 ◽  
Author(s):  
M J Quon ◽  
H Chen ◽  
B L Ing ◽  
M L Liu ◽  
M J Zarnowski ◽  
...  
Keyword(s):  
Cell Surface ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Expression Vectors ◽  
Regulatory Subunit ◽  
Dominant Negative Effect ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Receptor Tyrosine Kinase ◽  
Adipose Cells ◽  
Phosphatidylinositol 3

Insulin stimulates glucose transport in insulin target tissues by recruiting glucose transporters (primarily GLUT4) from an intracellular compartment to the cell surface. Previous studies have demonstrated that insulin receptor tyrosine kinase activity and subsequent phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to mediating the effect of insulin on glucose transport. We have now investigated the roles of 1-phosphatidylinositol 3-kinase (PI 3-kinase) and ras, two signaling proteins located downstream from tyrosine phosphorylation. Rat adipose cells were cotransfected with expression vectors that allowed transient expression of epitope-tagged GLUT4 and the other genes of interest. Overexpression of a mutant p85 regulatory subunit of PI 3-kinase lacking the ability to bind and activate the p110 catalytic subunit exerted a dominant negative effect to inhibit insulin-stimulated translocation of epitope-tagged GLUT4 to the cell surface. In addition, treatment of control cells with wortmannin (an inhibitor of PI 3-kinase) abolished the ability of insulin to recruit epitope-tagged GLUT4 to the cell surface. Thus, our data suggest that PI 3-kinase plays an essential role in insulin-stimulated GLUT4 recruitment in insulin target tissues. In contrast, over-expression of a constitutively active mutant of ras (L61-ras) resulted in high levels of cell surface GLUT4 in the absence of insulin that were comparable to levels seen in control cells treated with a maximally stimulating dose of insulin. However, wortmannin treatment of cells overexpressing L61-ras resulted in only a small decrease in the amount of cell surface GLUT4 compared with that of the same cells in the absence of wortmannin. Therefore, while activated ras is sufficient to recruit GLUT4 to the cell surface, it does so by a different mechanism that is probably not involved in the mechanism by which insulin stimulates GLUT4 translocation in physiological target tissues.

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