Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module

Wang, Haibin; Lo, Wen-Ting; Žagar, Andreja Vujičić; Gulluni, Federico; Lehmann, Martin; Scapozza, Léonardo; Haucke, Volker; Vadas, Oscar

doi:10.1016/j.molcel.2018.06.042

Cited by 46 publications

(48 citation statements)

References 40 publications

(58 reference statements)

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“…The upstream regulatory inputs that activate these PI3Ks remain largely unknown. With a structural concept for the regulation of PI3K-C2α activity now in place 146 , it will be exciting to understand how this applies to the other class II isoforms and how this integrates with other regulatory inputs such as phosphorylation or other posttranslational modifications. While PI3K-C2α is clearly essential for embryonic development 156,173 , we still know very little about its organismal role in post-natal stages.…”

Section: Discussionmentioning

confidence: 99%

“…As monomers lacking regulatory subunits, the class II PI3Ks have evolved a distinct mode of regulation that was recently uncovered for PI3K-C2 146 . In solution, the carboxyterminal PX-C2 module of PI3K-C2α folds back onto the kinase domain, thereby inhibiting membrane binding and catalytic activity.…”

Section: Activation Of Class II Pi3ksmentioning

confidence: 99%

“…In solution, the carboxyterminal PX-C2 module of PI3K-C2α folds back onto the kinase domain, thereby inhibiting membrane binding and catalytic activity. Only when recruited to the plasma membrane through its N-terminal interaction with clathrin 147,148 will cooperative binding to PI(4,5)P2 by the PX- 149 and C2-domain 150 unlock PI3K-C2α catalytic activity 146 (FIG. 4a).…”

Section: Activation Of Class II Pi3ksmentioning

confidence: 99%

“…Indeed, functional and cell biological approaches addressing the question of the class II PI3K lipid products have provided more insight than lipid analyses. These include the use of cell-permeant phosphoinositide-derivates 148,153,154 , visualization of local subcellular pools of phosphoinositides 63,146,148,154,155 , and an activation loop mutation that limits PI3K-C2α to PI3P synthesis 148,155,156 . Those studies that unambiguously identified the lipid product revealed that all class II PI3K isoforms produce PI(3,4)P2 in cells 63,148,154 .…”

Section: Lipid Products Of Class II Pi3ksmentioning

confidence: 99%

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PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

372

364

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Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids which directly activate signal transduction pathways. In addition to being frequently genetically-activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder which predisposes to lymphoma. The class II and III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an indirect impact on cell signalling. Here we summarize current knowledge on the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are stimulated. Areas covered include emerging evidence for isoform-specific regulation and function of Akt family members, potential non-cytotoxic actions of PI3K inhibitors in cancer and regulation of mTORC1 by class II and III PI3Ks. A deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes, and ultimately, in human disease. The cDNA cloning of the first catalytic subunit of a PI3K (p110, Ref. 1) in 1992 revealed close sequence similarity to the Saccharomyces cerevisiae Vps34 gene product, which was soon thereafter documented to possess PI3K activity in that it could convert phosphatidylinositol (PI) to its 3phosphorylated PI(3)P derivative 2. Subsequent bioinformatic and molecular biology approaches based on sequence homology of the kinase domain of these enzymes allowed the isolation of multiple PI3K genes from a range of organisms, with the Waterfield group proposing the now generally-accepted classification of the isoforms of PI3K 3-6. The main role of Vps34 in yeast in regulating the transport of proteins to the lysosome-like vacuole 7 indicates that regulation of vesicular traffic is the most ancient function of 3-phosphoinositides, with a role in signalling being a later addition in eukaryotic evolution 8. Genetic and pharmacological approaches have now uncovered the broad functions of the different PI3K isoforms, some of which are targets of the first approved PI3K inhibitors for the treatment of human cancer. The challenges faced in effectively targeting PI3K in disease have illustrated that much remains to be learned about PI3K biology. In this review, we summarize key recent insights into PI3K signalling and cell biology in mammals, for example, newly discovered human syndromes, resulting from constitutive activation of class I PI3Ks leading to tissue overgrowth 9 or immune deregulation 10, 11. Despite having been discovered over two decades ago 12, 13 , the class II PI3Ks remain the most enigmatic PI3K subfamily. Recent studies have started to uncover mechanisms by which these PI3Ks are regulated and how t...

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Section: Discussionmentioning

confidence: 99%

Section: Activation Of Class II Pi3ksmentioning

confidence: 99%

Section: Activation Of Class II Pi3ksmentioning

confidence: 99%

Section: Lipid Products Of Class II Pi3ksmentioning

confidence: 99%

See 2 more Smart Citations

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

372

364

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“…HDX-MS experiments were performed at the UniGe Protein Platform (University of Geneva, Switzerland). A similar protocol described previously was applied 25…”

Section: Hydrogen-deuterium Exchange Coupled To Mass Spectrometry (Hdmentioning

confidence: 99%

Naturally acquired blocking human monoclonal antibodies toPlasmodium vivaxreticulocyte binding protein 2b

Chan

Gandhirajan

Carias

et al. 2020

Preprint

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Plasmodium vivax preferentially invades reticulocytes and recognition of these cells is mediated by P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) binding to human Transferrin receptor 1 (TfR1) and Transferrin (Tf). Longitudinal cohort studies in Papua New Guinea, Thailand and Brazil show that PvRBP2b antibodies are correlated with protection against P. vivax infection and disease. Here, we isolated and characterized anti-PvRBP2b human monoclonal antibodies from two individuals in Cambodia with natural P. vivax infection. These antibodies bind with high affinities and map to different regions of PvRBP2b. Several human antibodies blocked PvRBP2b binding to reticulocytes and inhibited complex formation with human TfR1-Tf. We describe different structural mechanisms for functional inhibition, including either steric hindrance with TfR1-Tf or the reticulocyte membrane. These results show that naturally acquired human antibodies against PvRBP2b can inhibit its function which is important for P. vivax invasion.

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Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

Prever

Hsu

et al. 2022

Advanced Science

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Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy.

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Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module

Cited by 46 publications

References 40 publications

PI3K isoforms in cell signalling and vesicle trafficking

PI3K isoforms in cell signalling and vesicle trafficking

Naturally acquired blocking human monoclonal antibodies toPlasmodium vivaxreticulocyte binding protein 2b

Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer

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