PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling

Braccini, Laura; Ciraolo, Elisa; Campa, Carlo Cosimo; Perino, Alessia; Longo, Dario Livio; Tibolla, G.; Pregnolato, Marco; Cao, Yanyan; Tassone, Beatrice; Damilano, Federico; Laffargue, Muriel; Calautti, Enzo; Falasca, Marco; Norata, Giuseppe Danilo; Backer, Jonathan M.; Hirsch, Emilio

doi:10.1038/ncomms8400

Cited by 157 publications

(196 citation statements)

References 58 publications

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“…Some AKT targets localize to endomembrane surfaces (e.g., TSC2 (Menon et al, 2014; Roberts et al, 2004)), but others do not, such as nuclear-localized transcription factors (e.g., FoxO (Brunet et al, 1999)). This caveat notwithstanding, endomembranes contain PI3,4P 2 , and this mode of AKT regulation could represent a mechanism by which PI3,4P 2 and PIP 3 engage distinct pools of AKT (Braccini et al, 2015) (Figure 1A). This model is supported by studies on the PI3,4P 2 phosphatase and tumor suppressor INPP4B,, the loss of which leads to elevated PI3,4P 2 at endosomes and activation of AKT2 (Braccini et al, 2015; Fedele et al, 2010; Gewinner et al, 2009; Li Chew et al, 2015).…”

Section: Upstream Regulation Of Aktmentioning

confidence: 99%

AKT/PKB Signaling: Navigating the Network

Manning

Toker

2017

Cell

2,753

2,595

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The Ser/Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of Akt, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type-2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.

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Section: Upstream Regulation Of Aktmentioning

confidence: 99%

AKT/PKB Signaling: Navigating the Network

Manning

Toker

2017

Cell

2,753

2,595

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“…Consistent with this idea, APOE ε4, but not APOE ε3, in a thiorphan-treated APP mouse model of AD, expands lysosomal compartments, increases Aβ co-localization with lysosomes, and causes learning and memory impairment (Belinson et al, 2008). Cholesterol, the principal lipid carried into neurons by ApoE, and a suspected AD risk factor (Chen et al, 2014a; Chen et al, 2014b), also induces neuronal rab5 activation and endocytic upregulation when administered to animals through a high-fat diet (Braccini et al, 2015). Evidence suggests that membrane cholesterol may also influence v-ATPase function more directly.…”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

398

329

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Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

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“…Class II PI3K interacts with Rab5 and thereby controls endosomal activation of AKT 83 . The class III PI3K vacuolar protein sorting-associated protein 34 (VPS34, also known as PI3K catalytic subunit type 3), is tethered to endosomal membranes and directs the trafficking of proteins and vesicles, thus contributing to phagocytosis and autophagy 81 .…”

Section: Biology Of Mtor Complexesmentioning

confidence: 99%

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

2015

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Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of Tfollicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling

Cited by 157 publications

References 58 publications

AKT/PKB Signaling: Navigating the Network

AKT/PKB Signaling: Navigating the Network

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

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