Direct Regulation of the
            <i>Akt</i>
            Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate

Franke, Thomas; Kaplan, David R.; Cantley, Lewis C.; Toker, Alex

doi:10.1126/science.275.5300.665

Cited by 1,372 publications

(1,085 citation statements)

References 14 publications

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“…Since MAP kinase activation is not required for potassium-mediated survival 41 while downregulation of PI3kinase pathway occurs during potassium-deprivation-induced cell death, 47 we studied the effect of myc-tau overexpression on the Akt/protein kinase B serin/threonin kinase, a downstream target of PI-3 kinase. 48 We found that in neurons expressing tau and undergoing apoptosis, the extent of phosphoAkt was maintained at control levels, while, as also previously surmised, in control apoptotic neurons, or in neurons infected with Lac-Z, it was markedly reduced ( Figure 7a, b).…”

Section: Discussionsupporting

confidence: 85%

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

et al. 2003

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Although the role of the microtubule-binding domain of the tau protein in the modulation of microtubule assembly is widely established, other possible functions of this protein have been poorly investigated. We have analyzed the effect of adenovirally mediated expression of two fragments of the Nterminal portion -free of microtubule-binding domain -of the tau protein in cerebellar granule neurons (CGNs). We found that while the expression of the tau (1-230) fragment, as well as of full-length tau, inhibits the onset of apoptosis, the tau (1-44) fragment exerts a powerful toxic action on the same neurons. The antiapoptotic action of tau (1-230) is exerted at the level of Akt-mediated activation of the caspase cascade. On the other hand, the toxic action of the (1-44) fragment is not prevented by inhibitors of CGN apoptosis, but is fully inhibited by NMDA receptor antagonists. These findings point to a novel, physiological role of the N-terminal domain of tau, but also underlay that its possible proteolytic truncation mediated by apoptotic proteases may generate a highly toxic fragment that could contribute to neuronal death.

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Section: Discussionsupporting

confidence: 85%

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

et al. 2003

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“…There is a growing body of evidence to suggest that PtdIns(3,4)P2 is critically required for the full activation of Akt as compared with PtdIns(3,4,5)P3, which further strengthens our observation 37,38 . Interestingly, inhibition of the PI3K signalling by wortmannin lead to partial restoration of INPP4A expression and resolution of airway PV and PB denote perivascular and peribronchial inflammation, respectively.…”

Section: Discussionsupporting

confidence: 83%

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

et al. 2012

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Inositol polyphosphate phosphatases regulate the magnitude of phosphoinositide-3 kinase signalling output. Although inositol polyphosphate-4-phosphatase is known to regulate phosphoinositide-3 kinase signalling, little is known regarding its role in asthma pathogenesis. Here we show that modulation of inositol polyphosphate-4-phosphatase alters the severity of asthma. Allergic airway inflammation in mice led to calpain-mediated degradation of inositol polyphosphate-4-phosphatase. In allergic airway inflammation models, preventing inositol polyphosphate-4-phosphatase degradation by inhibiting calpain activity, or overexpression of inositol polyphosphate-4-phosphatase in mouse lungs, led to attenuation of the asthma phenotype. Conversely, knockdown of inositol polyphosphate-4-phosphatase severely aggravated the allergic airway inflammation and the asthma phenotype. Interestingly, inositol polyphosphate-4-phosphatase knockdown in lungs of naive mice led to spontaneous airway hyper-responsiveness, suggesting that inositol polyphosphate-4-phosphatase could be vital in maintaining the lung homeostasis. We suggest that inositol polyphosphate-4-phosphatase has an important role in modulating inflammatory response in asthma, and thus, uncover a new understanding of the complex interplay between inositol signalling and asthma, which could provide alternative strategies in asthma management. P hosphoinositide signalling, from phosphoinositide-3-kinase (PI3K) activation to Akt phosphorylation, critically regulates cellular functions, such as cell growth, differentiation, proliferation, survival and motility 1 . In response to growth factor stimuli, activation of PI(3)Ks leads to generation of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 at the plasma membrane. The intracellular concentration of PtdIns(3,4,5)P3 is controlled by a 3-phosphatase known as phosphatase and tensin homologue (PTEN) 2 or by 5-phosphatases (SHIP) 3 , resulting in the production of PtdIns(4,5)P2 and PtdIns(3,4)P2, respectively. PtdIns(3,4)P2, in turn, gets degraded by inositol polyphosphate-4-phosphatase (INPP4) to form PtdIns(3)P 4 . Genotypic variations in type I INPP4 (INPP4A), which is a regulatory checkpoint in phosphoinositide signalling, have previously been shown to be associated with increased risk of asthma 5,6 . Although other phosphoinositide phosphatases, PTEN and SHIP, have been shown to importantly regulate T-cell activation 7,8 , suppress B-cell lymphoma 9 and have protective roles in allergic airway inflammation (AAI) 10,11 , the functional role of INPP4A, in this context, is not known. As PtdIns(3,4)P2, but not PtdIns(3,4,5)P3, potently activates Akt 12 , INPP4A effectively terminates the PI3K-Akt signalling cascade.Asthma is characterized by episodic bronchoconstriction due to airway inflammation, remodelling and hyper-responsiveness 13 . Metabolic origins of asthma in obese subjects with minimal inflammatory cell infiltrate are an active topic of research 14 . Current understanding and treatment of asthma focuses on inhibiting airway inflamma...

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“…PI3K/AKT is a crucial pathway in carcinogenesis and is deregulated in various tumours including cervical cancer 8, 18, 19. Mutation data from many independent studies showed mutations in PIK3CA and PTEN in various proportions in cervical cancer (13%‐23% in PIK3CA, 5%‐8% in PTEN) 20.…”

Section: Discussionmentioning

confidence: 99%

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

Chen

Sun

et al. 2018

J Cellular Molecular Medi

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Cervical cancer continues to be among the most frequent gynaecologic cancers worldwide. The phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathway is constitutively activated in cervical cancer. Inositol polyphosphate 4‐phosphatase type II (INPP4B) is a phosphoinositide phosphatase and considered a negative regulatory factor of the PI3K/AKT pathway. INPP4B has diverse roles in various tumours, but its role in cervical cancer is largely unknown. In this study, we investigated the role of INPP4B in cervical cancer. Overexpression of INPP4B in HeLa, SiHa and C33a cells inhibited cell proliferation, metastasis and invasiveness in CCK‐8, colony formation, anchorage‐independent growth in soft agar and Transwell assay. INPP4B reduced the expression of some essential proteins in the PI3K/AKT/SGK3 pathway including p‐AKT, p‐SGK3, p‐mTOR, phospho‐p70S6K and PDK1. In addition, overexpression of INPP4B decreased xenograft tumour growth in nude mice. Loss of INPP4B protein expression was found in more than 60% of human cervical carcinoma samples. In conclusion, INPP4B impedes the proliferation and invasiveness of cervical cancer cells by inhibiting the activation of two downstream molecules of the PI3K pathway, AKT and SGK3. INPP4B acts as a tumour suppressor in cervical cancer cells.

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Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate

Cited by 1,372 publications

References 14 publications

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

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