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Cells survive, proliferate, and differentiate by interpreting the signals from the environment and translating them into the right output. If signaling goes awry, even in a few cells, the whole organism is at risk. We focus on signaling by the RAF/MEK/ERK pathway, an evolutionarily conserved kinase module which relays signals through consecutive phosphorylation of proteins arranged in three tiers. Constitutive activation of the pathway is a key event in several human malignancies and developmental disorders. Thus, proteins in this pathway are attractive therapeutic targets.
Strikingly, the pathway increases in complexity with evolution - from one paralog in simple organisms to three RAF, two MEK and two ERK paralogs in vertebrates. We investigate the essential roles of RAF and MEK paralogs and have discovered that they are indispensable for pathway cross‐talk, with functional consequences for homeostasis at the molecular, cellular, and organismal level.
The lab continues to focus on deciphering signaling pathways in the context of the whole organism, using a blend of genetics, molecular biology, biochemistry and cell biology. Since the essential functions of RAF and MEK paralogs are based primarily on their ability to undergo protein‐protein interactions with components of other signaling pathways, we are currently using an array of proximity labeling techniques coupled with mass spectrometry to understand the spatiotemporal context in which these complexes operate. To investigate the functional consequences of pathway perturbation, we rely mainly on primary cells and deploy single cell analysis of signaling pathways combined with single cell RNA‐seq to understand how RAF and MEK paralogs control cell fate decision.
Manuela is passionate about educating the next generation of scientists. She is the Director of the Vienna BioCenter PhD Program, a graduate school of the University of Vienna and Medical University of Vienna (link to the program website) and coordinates the FWF-funded PhD track “Signaling Mechanisms In Cellular Homeostasis”.
Hematopoietic stem cells (HSC) generate all cells in the blood, and are thus essential for our survival. HSC are rapidly activated when new blood is needed, but must go back to a dormant state lest the HSC compartment is exhausted. The fine balance between activation and dormancy is maintained by a negative feedback mechanism emanating from activated ERK and terminating ERK and AKT signaling.
The MEK paralog MEK1 dims signaling through the prosurvival PI3K/AKT pathway. Once modified by its substrate activated ERK, MEK1 binds to the lipid phosphatase PTEN and promotes its translocation to the plasma membrane. Here, PTEN breaks down the lipid second messenger PIP3, stopping AKT signaling. Thus, MEK1 balances signaling through two cascades that regulate cell proliferation and survival.
Activation of the RAF paralog RAF1 by growth factors and oncogenes generates distinct phosphorylated species which interact with the paralog BRAF, or with the cytoskeleton-based ROKα kinase. The BRAF complex is formed first and regulates ERK activation and proliferation, the ROKα complex regulates migration. RAF1 can be viewed as a moonlighting protein evolved to integrate distinct cell functions.
RAF1 ablation prevents the development and causes the regression of RAS-driven epidermal and lung tumors. In this system, RAS promotes complex formation between RAF1 and ROKα. RAF1 operates as an endogenous inhibitor of ROKα, which when unchecked induces exit from cell cycle and promotes keratinocyte differentiation.
RAF1 is required for RAS-driven lung and skin tumorigenesis. However in hepatocellular carcinoma (HCC) RAF1 puts the breaks on the proliferation of malignant hepatocytes, the actual tumor cells; therefore, and unexpectedly, RAF1 is a negative regulator of HCC. On the other hand, RAF1 is required in inflammatory cells of the tumor stroma to create an environment which stimulates HCC growth
An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion.
Baumgartner, Christian; Toifl, Stefanie; Farlik, Matthias; Halbritter, Florian; Scheicher, Ruth; Fischer, Irmgard; Sexl, Veronika; Bock, Christoph; Baccarini, Manuela
MEK1 Is Required for PTEN Membrane Recruitment, AKT Regulation, and the Maintenance of Peripheral Tolerance.
Zmajkovicova, Katarina,Jesenberger, Veronika, Catalanotti,Federica, Baumgartner, Christian, Reyes, Gloria und Manuela Baccarini
A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis.
Jeric, Ines; Maurer, Gabriele; Cavallo, Anna Lina; Raguz, Josipa; Desideri, Enrico; Tarkowski, Bartosz; Parrini, Matthias; Fischer, Irmgard; Zatloukal, Kurt; Baccarini, Manuela
Project title: “MEK1 complexes regulating the timing and strength of ERK and AKT signals" (P26874)
Project title: “Role of MEK1 signaling in the regulation of hematopoiesis and leukemogenesis" (P 26303)
Project title: “Rolle der Raf Kinasen in Angiogenesis"
Project title: “The multi-scale dynamics of signal transduction: dissecting the MAPK pathway”