Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Chen, Kai‐En; Tillu, Vikas A.; Chandra, Mintu; Collins, Brett M.

doi:10.1016/j.str.2018.08.010

Cited by 30 publications

(38 citation statements)

References 63 publications

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“…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%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

373

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: Activation Of Class II Pi3ksmentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

373

364

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“…PI3K effectors (class 2): The group of PI3K contains several domains with the ability to be associated to the PM, such as C2, the PX, and the PI3K_C2 domains. Recent biochemical studies have shown cooperative binding of the C2 and PX domains with affinities in complex with different phosphoinositides in the range of 4.5 to 52 μM [50]. An important source of phosphoinositide production at the PM are PI3K's themselves.…”

Section: Raf Effectors (Class 1)mentioning

confidence: 99%

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

et al. 2020

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Cancer is the second leading cause of death globally, and colorectal cancer (CRC) is among the five most common cancers. The small GTPase KRAS is an oncogene that is mutated in~30% of all CRCs. Pharmacological treatments of CRC are currently unsatisfactory, but much hope rests on network-centric approaches to drug development and cancer treatment. These approaches, however, require a better understanding of how networks downstream of Ras oncoproteins are connected in a particular tissue contexthere colon and CRC. Previously we have shown that competition for binding to a 'hub' protein, such as Ras, can induce a rewiring of signal transduction networks. In this study, we analysed 56 established and predicted effectors that contain a structural domain with the potential ability to bind to Ras oncoproteins and their link to pathways coordinating intestinal homoeostasis and barrier function. Using protein concentrations in colon tissue and Ras-effector binding affinities, a computational network model was generated that predicted how effectors differentially and competitively bind to Ras in colon context. The model also predicted both qualitative and quantitative changes in Ras-effector complex formations with increased levels of active Rasto simulate its upregulation in cancersimply as an emergent property of competition for the same binding interface on the surface of Ras. We also considered how the number of Ras-effector complexes at the membrane can be increased by additional domains present in some effectors that are recruited to the membrane in response to specific conditions (inputs/stimuli/growth factors) in colon context and CRC.

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“…Similar to the Class I PI3K p110s, these enzymes possess RBD, C2, helical and catalytic domains, but also possess a poorly‐structured N‐terminal region, in addition to a C‐terminal region containing C2 and PX domains [14,95]. Understanding of Class II PI3K regulation is in its infancy, but for PI3KC2α, the N‐terminal region has been shown to support plasma membrane recruitment of the enzyme via interactions with clathrin [96,97], while the C2 and PX domains interact with phosphoinositides such as PtdIns(4,5)P 2 to release an autoinhibitory mechanism to enable catalytic activity [98–100]. It is likely that multiple further interactions with proteins and lipids can regulate the function of the Class II PI3Ks and, as for the Class I PI3Ks, specificity within such interactions is likely to guide differential usage of the three Class II isoforms [93].…”

Section: Class II Pi3ksmentioning

confidence: 99%

PI3K inhibitors in thrombosis and cardiovascular disease

Durrant

Hers²

2020

Clinical & Translational Med

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Phosphoinositide 3‐kinases (PI3Ks) are lipid kinases that regulate important intracellular signalling and vesicle trafficking events via the generation of 3‐phosphoinositides. Comprising eight core isoforms across three classes, the PI3K family displays broad expression and function throughout mammalian tissues, and the (patho)physiological roles of these enzymes in the cardiovascular system present the PI3Ks as potential therapeutic targets in settings such as thrombosis, atherosclerosis and heart failure. This review will discuss the PI3K enzymes and their roles in cardiovascular physiology and disease, with a particular focus on platelet function and thrombosis. The current progress and future potential of targeting the PI3K enzymes for therapeutic benefit in cardiovascular disease will be considered, while the challenges of developing drugs against these master cellular regulators will be discussed.

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Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α

Cited by 30 publications

References 63 publications

PI3K isoforms in cell signalling and vesicle trafficking

PI3K isoforms in cell signalling and vesicle trafficking

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

PI3K inhibitors in thrombosis and cardiovascular disease

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