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Decision making in the endosomal compartment through phosphoinositides and myotubularin-related-proteins

English title Decision making in the endosomal compartment through phosphoinositides and myotubularin-related-proteins
Applicant Berger Philipp
Number 118351
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Cellular Biology, Cytology
Start/End 01.11.2007 - 30.04.2011
Approved amount 292'658.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Structural Research

Keywords (5)

myotubularin; phosphoinositide; receptor tyrosine kinase; signaling; charcot-marie-tooth disease

Lay Summary (English)

Lead
Lay summary
We are interested how external signals are propagated within eukaryotic cells. External signals (growth factors) bind to receptors on the plasma membrane which transmit the signal to the interior of the cell. Growth factors have the ability to generate several independent signals. We study how these signals are sorted within cells and how they are switched off.The endosomal compartment functions as an initial meeting point for internalized activated receptors. Multiple signals such as ubiquitination or phosphorylation of proteins or the phosphoinositide content of membranes are integrated at this place to determine the fate of internalized cargo. Our project focuses on the relevance of phosphoinositides. The significance of phosphoinositides is supported by the fact that mutations in many phosphoinositide-metabolizing enzymes have been associated with human diseases and that several intracellular pathogens secrete phosphoinositide phosphatases to allow their survival. Myotubularin-related-protein-2 (MTMR2) is an example of a disease-associated phosphoinositide-metabolizing enzyme. It dephosphorylates PI-3,5-P2 to PI-5-P and PI-3-P to phosphatidylinositol. MTMR2 and another myotubularin-related-protein, Set-binding-factor-2 (SBF2)/MTMR13, were identified as disease causing genes in Charcot-Marie-Tooth disease types 4B1 and 4B2, respectively. Our previous work points to a critical function of myotubularin-related-proteins in receptor tyrosine kinase sorting, degradation and signaling.We will use the newly available tools for multiprotein expression (MultiBac) in insect cells to purify MTMR containing complexes and determine their high resolution structures with X-ray crystallography and small angle X-ray scattering. In addition, we will adapt the MultiBac system for the expression of multiple proteins in mammalian cells. This allows the expression of several fluorescently tag proteins in a cell from a single vector and the live observation of a cell after a stimulation.Our results will provide insight into how MTMR2 and MTMR13/SBF2 regulate the sorting of receptor tyrosine kinases and their corresponding signals. The outcome of this process is crucial for human health and disease.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
121315 Upgrading the light microscopy facility at PSI with total internal reflection fluorescence microscopy (TIRFM) 01.07.2008 R'EQUIP

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