Cracking the context-specific PI3K signaling code

Madsen, Ralitsa R.; Vanhaesebroeck, Bart

doi:10.1126/scisignal.aay2940

Cited by 60 publications

(49 citation statements)

References 164 publications

(191 reference statements)

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“…These are detected by proteins with specialised phosphoinositide-binding domains, with AKT representing one of the most studied examples. Through AKT-dependent and -independent effectors, the PI3K pathway orchestrates an array of diverse phenotypic modules whose execution is highly context-dependent [8]. Negative feedback loops and cross-talk with other pathways are omitted for clarity.…”

Section: Pi3k Signalling: the Pathway That Seems To Do It Allmentioning

confidence: 99%

“…While PI3K signalling might be seen as capable of regulating most major cellular processes ( Figure 1), its output is usually rather specific and highly context-dependentgoverned by cell-specific gene expression programmes, signalling thresholds and environmental context [8]. Considering PI3K signalling as a 'pathway' is itself a simplification used to conceptualise a complicated network of signalling components.…”

Section: Pi3k Signalling: the Pathway That Seems To Do It Allmentioning

confidence: 99%

“…H1047R) also promote constitutive ligand-independent PI3K signalling [3]. Such differences could give rise to altered signalling dynamics and feedback regulation [8], which in turn may impinge on stemness regulation through distinct mechanisms.…”

Section: A Note On Contextmentioning

confidence: 99%

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PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.

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Section: Pi3k Signalling: the Pathway That Seems To Do It Allmentioning

confidence: 99%

Section: Pi3k Signalling: the Pathway That Seems To Do It Allmentioning

confidence: 99%

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PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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“…In the latter case, CFTR acts as a signalling hub by approximating many partners, akin to the role of NDPK in Ras signalling complexes [44]. Emerging data suggest that other signalling pathways implicated in cancer progression, for example PI3K signalling may also have opposing outcomes in a context-dependent manner [45]. Therefore, experiments carried out in developmental models in vivo have been required to unravel the biological functions of NM23/NDPK family members (reviewed in [46]).…”

Section: Introduction: Nm23-h1 the First Metastasis Suppressormentioning

confidence: 99%

The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Mátyási

Farkas

Kopper

et al. 2020

Pathol. Oncol. Res.

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Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for nonmetastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/ Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.

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“…Phosphatidylinositol 3-kinase (PI3K)/AKT signaling is an important pathway for controlling melanogenesis and it is frequently found to be active in melanoma cells. In response to hormones and growth factors, the serine/threonine protein kinase AKT binds to PI3K phospholipid product phosphatidylinositol 3,4,5-trisphosphate on the plasma membrane where it is activated by phosphorylation on threonine 308 and serine 473 [17]. The properties of a wide range of proteins are sensitive to phosphorylation by AKT.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

Perdomo

Quintana

González

et al. 2020

IJMS

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Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3β seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3β. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

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Cracking the context-specific PI3K signaling code

Cited by 60 publications

References 164 publications

PI3K in stemness regulation: from development to cancer

PI3K in stemness regulation: from development to cancer

The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

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