Class II PI3K Functions in Cell Biology and Disease

Gulluni, Federico; Santis, Maria Chiara De; Margaria, Jean Piero; Martini, Miriam; Hirsch, Emilio

doi:10.1016/j.tcb.2019.01.001

Cited by 105 publications

(100 citation statements)

References 107 publications

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“…1) are both reactive to shear stress in ciliated cells. As the main known enzymatic function of PI3KC2α is to synthesize PI3P 22 , we tested whether the shear stress response could also mobilize a dedicated pool of PI3P membranes at the PC vicinity. We thus monitored and quantified the local changes in PI3P-positive structures at the PC basal body area (see scheme on Fig.…”

Section: Resultsmentioning

confidence: 99%

“…11a, b, wildtype condition) and puncta quantification ( Supplementary Fig. 11c, d, wild-type condition), the kinase-inactive PI3KC2α (PI3KC2α K inact ), which lacks the ability to produce PI3P 22,37 , was unable to do so ( Supplementary Fig. 11a-d, PI3KC2α K inact condition), illustrating the crucial importance of PI3KC2α associated PI3P synthesis in response to shear stress.…”

Section: Resultsmentioning

confidence: 99%

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PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

et al. 2020

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Cells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation. Here we report that PI3KC2α, required for ciliogenesis and PC functions, promotes the synthesis of a local pool of PI3P upon shear stress. We show that PI3KC2α depletion in cells subjected to shear stress abolishes ciliogenesis as well as the autophagy and related cell size regulation. We finally show that PI3KC2α and VPS34, the two main enzymes responsible for PI3P synthesis, have different roles during autophagy, depending on the type of cellular stress: while VPS34 is clearly required for starvation-induced autophagy, PI3KC2α participates only in shear stress-dependent autophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

et al. 2020

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“…Although the relative quantitative contribution from each of the routes during EGFR intracellular trafficking is not precisely understood, it is generally accepted that degradation from PI(3,4,5)P 3 contributes to a significant fraction of PI(3,4)P 2 in intracellular vesicles upon RTK activation (36,37). Additional studies are required to determine whether class II PI3Ks can function in an analogous manner to INPP4B in TNBC etiology, especially given their importance in physiology and disease (83).…”

Section: Discussionmentioning

confidence: 99%

The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer

et al. 2020

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Inactivation of the tumor suppressor lipid phosphatase INPP4B is common in triplenegative breast cancer (TNBC). We generated a genetically engineered TNBC mouse model defi cient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for AKT and MEK gene signatures. Consequently, mice with INPP4B defi ciency are more sensitive to PI3K or MEK inhibitors compared with WT mice. Mechanistically, we found that INPP4B defi ciency increases PI(3,4)P 2 levels in endocytic vesicles but not at the plasma membrane. Moreover, INPP4B loss delays degradation of EGFR and MET, while promoting recycling of receptor tyrosine kinases (RTK), thus enhancing the duration and amplitude of signaling output upon growth factor stimulation. Therefore, INPP4B inactivation in TNBC promotes tumorigenesis by modulating RTK recycling and signaling duration. SIGNIFICANCE: Inactivation of the lipid phosphatase INPP4B is frequent in TNBC. Using a genetically engineered mouse model, we show that INPP4B functions as a tumor suppressor in TNBC. INPP4B regulates RTK traffi cking and degradation, such that loss of INPP4B prolongs both PI3K and ERK activation.

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“…Class II PI3Ks have 2 characteristic C2 domains, a catalytic domain, a Ras‐binding domain, and a specific phosphoinositide‐binding PX domain. Recent reviews detailed the broad actions of PI3KC2α and PI3KC2β in several cellular functions with their major implications in vesicular trafficking …”

Section: Pi3kc2α‐dependent Ptdins3p Pool Is Essential For Membrane Momentioning

confidence: 99%

Phosphatidylinositol 3‐monophosphate: A novel actor in thrombopoiesis and thrombosis

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Levade

Bellio

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Phosphoinositides are lipid second messengers regulating in time and place the formation of protein complexes involved in the control of intracellular signaling, vesicular trafficking, and cytoskeleton/membrane dynamics. One of these lipids, phosphatidylinositol 3 monophosphate (PtdIns3P), is present in small amounts in mammalian cells and is involved in the control of endocytic/endosomal trafficking and in autophagy. Its metabolism is finely regulated by specific kinases and phosphatases including class II phosphoinositide 3‐kinases (PI3KC2s) and the class III PI3K, Vps34. Recently, PtdIns3P has emerged as an important regulator of megakaryocyte/platelet structure and functions. Here, we summarize the current knowledge in the role of different pools of PtdIns3P regulated by class II and III PI3Ks in platelet production and thrombosis. Potential new antithrombotic therapeutic perspectives based on the use of inhibitors targeting specifically PtdIns3P‐metabolizing enzymes will also be discussed. Finally, we provide report of new research in this area presented at the International Society of Thrombosis and Haemostasis 2019 Annual Congress.

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Class II PI3K Functions in Cell Biology and Disease

Cited by 105 publications

References 107 publications

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer

Phosphatidylinositol 3‐monophosphate: A novel actor in thrombopoiesis and thrombosis

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