Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks

Malik, Nazma; Macartney, Thomas; Hornberger, Annika; Anderson, Karen E.; Tovell, Hannah; Prescott, Alan R.; Alessi, Dario R.

doi:10.1042/bcj20170650

Cited by 34 publications

(52 citation statements)

References 60 publications

(86 reference statements)

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“…This follows an upregulation of PI(3,4,5)P 3 in MEFs at the same time points. Similar results on pAkt were also reported in human embryonic kidney cells in response to insulin-like growth factor 1 added for 5 min (50). pAkt upregulation in SHIP2-depleted cells is thus transient; it is not observed when cells are maintained in serum.…”

Section: Pi 5-phosphatases and Pi(34)p 2 A New Signal Moleculesupporting

confidence: 85%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4- and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for INPP5A, they all catalyze the dephosphorylation of PI(4,5)P2 and/or PI(3,4,5)P3 at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P3 and also participate in fine-tuning regulatory mechanisms of PI(3,4)P2 and PI(4,5)P2. Second messenger functions have been demonstrated for PI(3,4)P2 in invadopodium maturation and in lamellipodia formation. PI 5-phosphatases can use several substrates on isolated enzymes, and it has been challenging to establish their real substrate in vivo. PI(4,5)P2 has multiple functions in signaling, including interaction with scaffold proteins, ion channels, and cytoskeleton proteins. PI 5-phosphatase isoenzymes have been individually implicated in human diseases, such as the oculocerebrorenal syndrome of Lowe, through mechanisms which include lipid-controlling. Oncogenic and tumor suppressive functions of PI 5-phosphatases have also been reported in different cell contexts. The mechanisms responsible for genetic diseases and for tumor suppressor or oncogenic functions are not fully understood. The regulation of PI 5-phosphatases is thus crucial in understanding cell functions.

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Section: Pi 5-phosphatases and Pi(34)p 2 A New Signal Moleculesupporting

confidence: 85%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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“…However, 3-methyladenine is not selective for Vps34, and highly-selective Vps34 inhibitors have now been developed [201][202][203][204][205][206] . These have been used to confirm the role of Vps34 in autophagy and vesicular trafficking, to identify putative autophagy substrates and autophagy cargo receptors 202 and a possible involvement of Vps34 in the regulation of signalling 201,207,208 .…”

Section: Commented [Bv28]mentioning

confidence: 99%

“…Upon growth factor stimulation (such as by IGF1), SGK3 is recruited via its PX domain to the endosomal membrane by PI(3)P generated by two sources, namely by Vps34 complex II (Refs. 201,207 ) and by sequential dephosphorylation of PIP3 by the SHIP/INPP4 lipid phosphatases 217 . Growth factor-activated PDK1 and mTORC2, which have been found on endosomal membranes 218,219 then activate SGK3 kinase activity in an analogous way to activation of Akt, by phosphorylation of the activation loop in the kinase-domain (PDK1) and of the C-terminus (mTORC2) 201,207 .…”

Section: Regulation Of Protein Kinase Signalling By Vps34 Like the Cmentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

371

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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“…However, the currently known SGK-3 inhibitors have poor IC 50 values and selectivity. 313 Thus, it seems that optimization and characterization of an SGK3-specific PROTAC is particularly attractive.…”

Section: Sgk3mentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

432

414

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks

Cited by 34 publications

References 60 publications

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

PI3K isoforms in cell signalling and vesicle trafficking

PROTACs: great opportunities for academia and industry

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