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Research area
We are interested in the molecular mechanism that coordinate cell signaling and membrane traffic, in particular during cell surface remodelling. Cell surface remodelling requires the selective degradation of transmembrane proteins in the lysosome. Defects in this essential degradation pathway contribute to hallmarks of cancer such as loss of cell polarity, defects in cell migration and enhanced proliferation and hence can be considered a tumor supressor pathway.
Cell surface remodelling. The ubiqutin dependent degradation of membrane proteins via the multivesicular body (MVB) pathway is mediated by the ESCRT and essential for cell surface remodelling.
A key step of receptor downregulation occurs on endosomes, where the endosomal complexes required for transport (ESCRTs) sort ubiquitinated cell surface receptors via the multivesicular body (MVB) pathway to the lumen of lysosomes for degradation. This essential, ESCRT-dependent, degradation pathway controls the repertoire of cell surface receptors.
Cell surface receptor downregulation requires the ESCRT machinery. Yeast cells expressing a GFP-tagged cell surface receptor (Mup1-GFP, green). In non-stimulated cells (- methionine), the receptors are at the cell surface. Upon stimulation they are transported into the vacuole (limiting vacuole membrane, FM4-64 in red). In ESCRT mutants, membrane proteins are not transported into the vacuole but accumulate instead on aberrant endosomes (Class E compartment).
Consequently, the ESCRT machinery is involved in diverse developmental processes and its dysfunction contributes to many diseases including cancer and neuro-degeneration. Moreover, the same ESCRT machinery is hijacked by viruses such as HIV to promote their release from host cells. Due to the universal function of the ESCRT machinery in eukaryotes, we use yeast as the best suited model system and a combination of biochemistry and imaging to address the following questions:
- How does the ESCRT machinery form MVB vesicles ?
- How is the activity of the ESCRT machinery regulated ?
- How do cells monitor the activity of the ESCRT machinery?
International collaborations
- Reinhard Faessler (MPI, Muenchen, GE)
- Prof. Scott D. Emr (Cornell University, Ithaca, NY)