Phosphoinositide Diversity, Distribution, and Effector Function: Stepping Out of the Box

Choy, Christopher H.; Han, Bong-Kwan; Botelho, Roberto J.

doi:10.1002/bies.201700121

Cited by 48 publications

(47 citation statements)

References 114 publications

(190 reference statements)

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“…phosphoinositides can modulate their metabolism and the effector response 37 and early data in platelets show that some minor species of PI(4,5)P2 become highly enriched upon stimulation 38 . While the functional implications of these observations remain to be determined, such analyses have the potential to uncover additional functional diversification of the cell's 3-phosphoinositide code.…”

mentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

389

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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mentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

389

364

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“…These lipids play various roles within the cell, e.g. PI(4)P is fairly widely distributed and has a well-established role in controlling cargo exit from the Golgi, while PI(5)P distribution is much more restricted and may play a limited role in modulating nuclear functions (35,36). Much attention has been paid to PI(3)P, which plays at least two major roles -by recruiting a range of adapter proteins to membranes it is critical to the endocytic pathway and to autophagosome biogenesis at the ER (35)(36)(37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, endogenous erlin1/2 complex was immunopurified from T3 cells with anti-erlin1 and its binding to a panel of immobilized lipids (35,36) was examined by probing for erlin2 (Fig 4). Surprisingly, no specific binding to cholesterol was discovered, but rather, binding to PI(4)P was detected ( Fig 4A).…”

Section: The Erlin1/2 Complex Specifically Binds Pi(3)p and The T65i mentioning

confidence: 99%

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

Wright

Bonzerato

Sliter

et al. 2018

Journal of Biological Chemistry

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The erlin1/2 complex is a ~2MDa endoplasmic reticulum membrane-located ensemble of the ~40kDa type II membrane proteins erlin1 and erlin2. The best-defined function of this complex is to mediate the ubiquitination of activated inositol 1,4,5-trisphosphate receptors (IP3Rs) and their subsequent degradation. However, it remains unclear how mutations of the erlin1/2 complex affect its cellular function and cause cellular dysfunction and diseases such as hereditary spastic paraplegia. Here, we used gene editing to ablate erlin1 or erlin2 expression to better define their individual roles in the cell and examined the functional effects of a spastic paraplegia-linked mutation to erlin2 (threonine to isoleucine at position 65; T65I). Our results revealed that erlin2 is the dominant player in mediating the interaction between the erlin1/2 complex and IP3Rs, and that the T65I mutation dramatically inhibits this interaction and the ability of the erlin1/2 complex to promote IP3R ubiquitination and degradation. Remarkably, we also discovered that the erlin1/2 complex specifically binds to phosphatidylinositol 3-phosphate, that erlin2 binds this phospholipid much more strongly than does erlin1, that the binding is inhibited by T65I mutation of erlin2, and that multiple determinants within the erlin2 polypeptide comprise the phosphatidylinositol 3-phosphate-binding site.Overall, these results indicate that erlin2 is the primary mediator of the cellular roles of the erlin1/2 complex and that disease-linked mutations of erlin2 can affect both IP3R processing and lipid binding.

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“…Within mammalian cell membranes, PtdIns accounts for ~10‐15 mol% of total phospholipids, while the various PPIn species only comprise an estimated ~2‐5% of the available PtdIns . However, despite their relatively low abundance, PPIn lipids are essential components of eukaryotic cell membranes where they facilitate the recruitment of peripheral membrane effectors, regulate the activities of integral membrane proteins, and serve as determinants of membrane identity . One of the first dedicated steps in PPIn synthesis is catalyzed by a group of enzymes called PtdIns 4‐kinases (PI4Ks), which selectively phosphorylate the four‐position of the PtdIns headgroup to generate mono‐phosphorylated PtdIns4P(Figure ).…”

Section: Production Of Polyphosphoinositide Species Within the Pmmentioning

confidence: 99%

“…In addition to essential roles during signal transduction, both PtdIns4P and PtdIns(4,5)P 2 directly control the recruitment and activity of protein complexes at the PM that are critical for membrane fusion, cytoskeletal dynamics, and vesicular trafficking . One of the most important recent discoveries in membrane biology, however, was the demonstration that PtdIns4P also serves as an essential component of non‐vesicular lipid transport cycles.…”

Section: Phosphatidylinositol 4‐phosphate Gradients and Non‐vesicularmentioning

confidence: 99%

Integrated regulation of the phosphatidylinositol cycle and phosphoinositide‐driven lipid transport at ER‐PM contact sites

Pemberton

Kim

Balla

2019

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Among the structural phospholipids that form the bulk of eukaryotic cell membranes, phosphatidylinositol (PtdIns) is unique in that it also serves as the common precursor for low-abundance regulatory lipids, collectively referred to as polyphosphoinositides (PPIn). The metabolic turnover of PPIn species has received immense attention because of the essential functions of these lipids as universal regulators of membrane biology and their dysregulation in numerous human pathologies. The diverse functions of PPIn lipids occur, in part, by orchestrating the spatial organization and conformational dynamics of peripheral or integral membrane proteins within defined subcellular compartments. The emerging role of stable contact sites between adjacent membranes as specialized platforms for the coordinate control of ion exchange, cytoskeletal dynamics, and lipid transport has also revealed important new roles for PPIn species. In this review, we highlight the importance of membrane contact sites formed between the endoplasmic reticulum (ER) and plasma membrane (PM) for the integrated regulation of PPIn metabolism within the PM. Special emphasis will be placed on non-vesicular lipid transport during control of the PtdIns biosynthetic cycle as well as toward balancing the turnover of the signaling PPIn species that define PM identity. K E Y W O R D SCRAL-TRIO, intracellular transport, lipid transfer protein, membrane contact sites, nonvesicular lipid transport, oxysterol-binding protein-related protein, phosphatidylinositol, phosphatidylinositol transfer protein, phosphoinositides, phospholipid metabolism, signal transduction, StARkin, TUbular LIPid-binding

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Phosphoinositide Diversity, Distribution, and Effector Function: Stepping Out of the Box

Cited by 48 publications

References 114 publications

PI3K isoforms in cell signalling and vesicle trafficking

PI3K isoforms in cell signalling and vesicle trafficking

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

Integrated regulation of the phosphatidylinositol cycle and phosphoinositide‐driven lipid transport at ER‐PM contact sites

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