Defining How Oncogenic and Developmental Mutations of PIK3R1 Alter the Regulation of Class IA Phosphoinositide 3-Kinases

Dornan, Gillian L.; Stariha, Jordan T B; Rathinaswamy, Manoj K.; Powell, Cameron J.; Boulanger, Martin J.; Burke, John E.

doi:10.1016/j.str.2019.11.013

Cited by 28 publications

(24 citation statements)

References 66 publications

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“…Virus generation and amplification for PI3Kγ constructs were carried out according to our standard protocol ( 58 ). The plasmid-encoding genes for insect cell expression were transformed into DH10MultiBac cells (MultiBac, Geneva Biotech) to generate baculovirus plasmid (bacmid) containing the genes of interest.…”

Section: Methodsmentioning

confidence: 99%

Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

et al. 2021

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The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. Here, we report the cryo–electron microscopy structure of a heterodimeric PI3Kγ complex, p110γ-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ–adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101–specific signaling events in vivo.

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Section: Methodsmentioning

confidence: 99%

Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

et al. 2021

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“…Besides, E 2 can combine with the estrogen receptor- α (ER- α ) and estrogen receptor- β (ER- β ) in the ovary [ 19 ]. ER- α combines with the subunit p85 in PI3K to activate AKT [ 20 , 21 ]. Meanwhile, mTOR is activated by AKT, which leads to the proliferation and development of follicles [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Electroacupuncture on the Gut Microbiome in Cisplatin-Induced Premature Ovarian Failure Mice

Guo

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Growing evidence showed that the gut microbiota was associated with premature ovarian failure (POF). Many clinical types of research had shown that electroacupuncture was effective in the treatment of POF. However, there was little research on regulating the gut microbiome of POF mice by electroacupuncture. Therefore, this study attempted to verify whether electroacupuncture could regulate the gut microbiome in POF mice. POF mice were established by being injected intraperitoneally with cisplatin (2 mg/kg) for 2 weeks. Guanyuan (CV4) and Sanyinjiao (SP6) were selected in the electroacupuncture-at-the-acupoints group (EA group). Nonacupoints around CV4 and SP6 were selected in the electroacupuncture-at-the-nonacupoints group (EN group). The EA group and EN group were treated for 3 weeks. The ovarian function was evaluated by histopathological and molecular assays. Meanwhile, the gut microbiome of all mice was detected by 16S rDNA sequencing. The results showed that EA could restore the estrous cycle and reduce the number of atresia follicles in POF mice. The levels of serum follicle-stimulating hormone and luteinizing hormone were decreased by EA. As well, the levels of serum estradiol, anti-Mullerian hormone, and β-glucuronidase were increased by EA. The relative expressions of PI3K, AKT, and mTOR were increased to promote the proliferation of ovarian cells in the EA group. According to the results of 16S rDNA sequencing, the abundance and diversity of the gut microbiome could be regulated by EA. The relative abundance of beneficial bacteria was increased by EA. The KEGG pathway analysis showed that the gut microbiome associated with the estrogen signaling pathway, oocyte maturation, and PI3K-AKT signaling pathway was regulated by EA.

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“…Akt is also known as protein kinase B and is the main downstream signaling molecule of PI3K. Activated Akt further acts on its downstream target proteins through phosphorylation and then plays its role in regulating cell proliferation, differentiation, migration, and glucose metabolism [ 23 , 24 ]. TOR is one of downstream target genes of Akt.…”

Section: Discussionmentioning

confidence: 99%

Role of Episamarcandin in Promoting the Apoptosis of Human Colon Cancer HCT116 Cells through the PI3K-Akt Signaling Pathway

Zhang

Sun

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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This study identifies the active ingredients of Ferula sinkiangensis and investigates the role and mechanism of episamarcandin in colon cancer cells. The silica gel column chromatography was utilized to separate the chemical components of Ferula sinkiangensis. Sephadex LH-20 and semipreparative HPLC were adopted for further separation and purification. The compound episamarcandin showed good anticolon cancer activity among the 13 monomeric compounds obtained. Its effects on the apoptosis, cell cycle, and invasion and migration of colon cancer HCT 116 cells and PI3K-Akt signaling pathway were further investigated. The results showed that, similar to positive control cisplatin, episamarcandin inhibited the proliferation, promoted the apoptosis, arrested cells at G0/G1 phase, and suppressed migration and invasion of HCT 116 cells. A large number of apoptotic HCT 116 cells were observed under a transmission electron microscope. Fluorescence real-time quantitative PCR and western blot analysis showed that episamarcandin increased the expression of PTEN, p53, and Bax and decreased the expression of P-Akt, Akt, mTOR, Bcl-xl, and Bcl-2. Conclusively, episamarcandin may inhibit cell proliferation, migration, and invasion and promote the apoptosis of human colon cancer HCT 116 cells possibly through the PI3K-Akt signaling pathway.

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Defining How Oncogenic and Developmental Mutations of PIK3R1 Alter the Regulation of Class IA Phosphoinositide 3-Kinases

Abstract: Highlightsd Oncogenic Q572 * variant of p85a leads to hyper-activation of p110a compared with p110dd HDX-MS revealed that Q572 * leads to disruption of all inhibitory interfaces in p110ad An SHORT syndrome mutation in p85a leads to decreased sensitivity to RTKs for p110a/d

Cited by 28 publications

References 66 publications

Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

Effects of Electroacupuncture on the Gut Microbiome in Cisplatin-Induced Premature Ovarian Failure Mice

Role of Episamarcandin in Promoting the Apoptosis of Human Colon Cancer HCT116 Cells through the PI3K-Akt Signaling Pathway

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