Lipid membranes not only delineate the outer boundaries of the cell; they also provide an effective way to compartmentalize biological reactions inside of cells. But membranes are far from being only passive barriers. They are highly dynamic signaling hotspots on which multiple pathways controlling cell physiology converge. The PI3K pathway is involved in cell growth, metabolism, and proliferation, and is frequently dysregulated in cancer. One particular signal transducer in the pathway is the serum and glucocorticoid-regulated protein kinase 3 (Sgk3), which is activated by the phospholipid phosphatidylinositol 3-phosphate (PI3P) generated downstream of growth factor signaling. Sgk3 has two domains – a lipid binding domain and a kinase domain that propagates the signal by phosphorylating an array of molecules that implement the appropriate change in cell behavior, called effector molecules. “PI3P has previously been thought of as a molecular anchor that simply ensures the correct localization of the kinase”, says first author Daniel Pokorny, who pursues his PhD studies in the group of Thomas Leonard. “Our findings add an additional role of this lipid in that it directly stimulates the kinase activity of Sgk3”.
The scientists reconstituted the activation of Sgk3 in real-time on synthetic membranes. They found that the two domains of Sgk3 communicate with each other. In the absence of PI3P, its PI3P-binding domain maintains the kinase domain in an inhibitory conformation. The scientists discovered that the PI3P binding pocket is inaccessible in this conformation, which raises the threshold PI3P concentration required to activate Sgk3. These findings have obvious consequences for the spatiotemporal activation of Sgk3. It was previously assumed that the active conformation of kinases such as Akt and Sgk3 must dissociate from the membrane in order to encounter and phosphorylate their targets. “The problem with this model is that it essentially uncouples kinase activity from the activating stimulus”, explains group leader Thomas Leonard. “Our work shows that Sgk3 still needs to be bound to PI3P in order for the kinase to actually propagate the signal”.
Sgk3 has been observed to be upregulated in some cancers that exhibit paradoxical hypoactivation of Akt. While its potential role in cancer makes it an attractive therapeutic target, developing highly specific kinase inhibitors has historically been quite challenging, since the ATP-binding pocket is highly conserved in all protein kinases. The scientists’ findings could help overcome this specificity problem for Sgk3. “The intramolecular interface between the two domains is unique to Sgk3”, says lead author Daniel Pokorny. “The interface is therefore a potential therapeutic target for allosteric inhibitors that would lock this kinase in a closed, inactive conformation by binding to the interface”.
Publication:
Daniel Pokorny, Linda Truebestein, Kaelin D. Fleming, John E. Burke, Thomas A. Leonard: In vitro reconstitution of Sgk3 activation by phosphatidylinositol 3-phosphate. Journal of Biological Chemistry, 2021.
18th Microsymposium on RNA Biology
The „Microsymposium on RNA Biology“ is an international conference that brings together young scientists, junior and senior group leaders, and company representatives from all over the world to present and discuss their latest findings in the exciting field of small RNAs and beyond. The Microsymposium was founded in 2005 and has established itself as the major small RNA meeting in Europe. It is organized by the four research institutions IMBA, IMP, GMI and the Max Perutz Labs as well as by the RNA community of the Vienna BioCenter.
Nickel impact on human health, from bacterial infections to cancer
Multiscale plant bioimaging using advanced microscopy
Parthenogenesis, cryptobiosis, and the survival in extreme environmental conditions
Evading ageing: Mitochondrial and proteostatic adaptations in oocytes
Genomes in Rhodnius prolixus symbiotic system
Stem cells, immune evasion and metastasis in colorectal cancer
Ubiquitin & Friends Symposium 2024
The Ubiquitin & Friends Symposium is an annual international meeting taking place in the beautiful capital of Austria, aiming to bring together scholars from various fields studying ubiquitin/Ubl biology and protein degradation in a personal, family-like atmosphere, as suggested by the name.
The evolution and development of mollusc shells
Unraveling the Complexity of Crossover Regulation in C. elegans
Dynamics of 3D Genome Structure and Function
How superworms can help to solve our plastic waste crisis
Title to be announced
New players in an old pathway: biology of methanogens of the TACK superphylum
Shaping morphogen gradients: from molecules to tissues and back
Title to be announced
Studying stressed cells by in situ structural biology
Exploring Microbial Resilience: Unravelling Escherichia coliand#x27;s Stress Response at the Level of Protein Synthesis
Arbuscular mycorrhiza development and function
Deep homology and deep diversity: Evolving genetic toolkits for making and sensing light
The evolution of cell type identity and tissue microecology at the fetal-maternal interface
The unanticipated roles of PICIs and phages in bacterial evolution
Chemical targeting of subcellular protein localization
Origin and diversification of gut-derived organs in chordates
Job's Dilemma for the Genome: Why Bad Things Happen to Good Chromosomes
Connections between carbon and nitrogen cycling in the ocean
Understanding how the DNA-loop-extruding protein complex Condensin folds a chromatinized genome into mitotic chromosomes
From Roads to Rivers? Occurrence and environmental fate of tire and road wear particles and of tire-related chemicals
FENS 2024 Satellite event: Home cage behavior monitoring at the interface of animal welfare and neuroscience
Striking physiology and cell biology of (marine) environmental microorganisms
Mechanisms controlling maintenance of cohesin dependent loops
Title to be announced