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All life is regulated by the reversible phosphorylation of proteins. The phosphorylation state of a protein determines its biochemical properties and biological functions and is regulated by the opposing catalytic forces of protein kinases and phosphatases. In this tug-of-war the role of the phosphatases has been neglected for a long time due to the misconception of phosphatases being promiscuous, non-specific enzymes that only set the stage for kinases. The reason for that resided in a lack of knowledge on the complex nature of these enzymes. With the growing knowledge on phosphatases their equal importance for many biological processes became clear. A major phosphoserine/-threonine phosphatase in the cell is protein phosphatase 2A (PP2A). PP2A stands for a large multisubunit holoenzyme family, each of which fulfills its own substrate specific tasks. We are trying to answer how the biogenesis of PP2A holoenzymes is regulated and what the substrates of PP2A holoenzymes are.
We study PP2A biogenesis in yeast and mammals using biochemical, genetic and immunological approaches. Key tools for our analysis are monoclonal antibodies with exquisite specificity. We generated the worldwide first and still unique antibody recognizing the PP2A carboxy-terminal methylation, a modification of the catalytic subunit essential for the assembly of PP2A holoenzymes with tumor-suppressive functions. Our analysis in yeast unraveled some of the basic principles of PP2A biogenesis and laid the foundation to the present PP2A biogenesis model. Despite the high degree of conservation much less is known about this process in higher eukaryotes. We generated a conditional knockout mouse of the PP2A chaperone PTPA and are analyzing the knockout phenotype on a molecular level. Detailed knowledge on mammalian PP2A biogenesis is required for novel therapeutic strategies such as SMAPs, recently developed drugs that restore the tumor-suppressive function of PP2A.
Egon Ogris studied medicine at the University of Vienna and obtained his MD in 1987. From 1992-1995 Egon was a postdoctoral fellow at the Dana-Farber Cancer Institute/Harvard Medical School in Boston. In 1995 he started his own group at the University of Vienna (now Medical University of Vienna), where he habilitated in 2000.
Two new papers from our lab now show that several antibodies recognizing the enzyme PP2A, and an antibody widely used in a technique called Myc tagging lack the precision for their intended tasks. The findings published in “Science Signaling” show that this and other Myc tag antibodies yield inconsistent results depending on the molecular surrounding of the tag, and that antibodies recognizing PP2A often prove to be unsuitable for measuring the activity of this enzyme.
Read the abstracts:
We have uncovered the function of PTPA as a PP2A activation chaperone. This activation step is coupled to the interaction with the structural PP2A subunit and is under surveillance of the PP2A methylesterase. Methylation of the PP2A catalytic subunit is an essential requirement for the assembly of trimeric holoenzymes.
The transient interaction between PP2A and its substrates cannot be detected by standard methods, which is the major reason for the lack of knowledge on the “true in vivo” substrates of PP2A. In collaboration with the Ammerer lab we developed a protein proximity assay termed M-TRACK, which makes it possible to detect and analyze such short-lived PPIs in vivo.
We generate monoclonal antibodies for research and diagnosis, offer a monoclonal antibody service and develop novel approaches to improve antibody specificity. Examples are antibodies specific for lamin A/C point-mutants to study laminopathies, for apolipoprotein E4 for Alzheimer’s risk assessment and the anti-BLUE/anti-RAINBOW antibodies for the western blot detection of protein markers.
Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.
Rasool, Reyaz Ur; O'Connor, Caitlin M; Das, Chandan Kanta; Alhusayan, Mohammed; Verma, Brijesh Kumar; Islam, Sehbanul; Frohner, Ingrid E; Deng, Qu; Mitchell-Velasquez, Erick; Sangodkar, Jaya; Ahmed, Aqila; Linauer, Sarah; Mudrak, Ingrid; Rainey, Jessica; Zawacki, Kaitlin P; Suhan, Tahra K; Callahan, Catherine G; Rebernick, Ryan; Natesan, Ramakrishnan; Siddiqui, Javed; Sauter, Guido; Thomas, Dafydd; Wang, Shaomeng; Taylor, Derek J; Simon, Ronald; Cieslik, Marcin; Chinnaiyan, Arul M; Busino, Luca; Ogris, Egon; Narla, Goutham; Asangani, Irfan A
Selective PP2A Enhancement through Biased Heterotrimer Stabilization.
Leonard, Daniel; Huang, Wei; Izadmehr, Sudeh; O'Connor, Caitlin M; Wiredja, Danica D; Wang, Zhizhi; Zaware, Nilesh; Chen, Yinghua; Schlatzer, Daniela M; Kiselar, Janna; Vasireddi, Nikhil; Schüchner, Stefan; Perl, Abbey L; Galsky, Matthew D; Xu, Wenqing; Brautigan, David L; Ogris, Egon; Taylor, Derek J; Narla, Goutham
PP2AC Phospho-Tyr307 Antibodies Are Not Specific for this Modification but Are Sensitive to Other PP2AC Modifications Including Leu309 Methylation.
Frohner, Ingrid E; Mudrak, Ingrid; Schüchner, Stefan; Anrather, Dorothea; Hartl, Markus; Sontag, Jean-Marie; Sontag, Estelle; Wadzinski, Brian E; Preglej, Teresa; Ellmeier, Wilfried; Ogris, Egon
Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition.
Frohner, Ingrid E; Mudrak, Ingrid; Kronlachner, Stephanie; Schüchner, Stefan; Ogris, Egon
The Myc tag monoclonal antibody 9E10 displays highly variable epitope recognition dependent on neighboring sequence context.
Schüchner, Stefan; Behm, Christian; Mudrak, Ingrid; Ogris, Egon
The Ogris lab is funded by service and royalty fees from antibody licensing agreements and the monoclonal antibody service facility of the Medical University of Vienna/Max Perutz Labs.
The Group Ogris participates in the special Doctoral Program "Molecular Mechanisms of Cell Signaling" reviewed and funded by the Austrian Research Fund FWF.
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