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Projekt
VCP/p97-governed sorting of mono-ubiquitinated proteins in the endocytic pathway
Antragsteller
Professor Dr. Hemmo Meyer
Fachliche Zuordnung
Zellbiologie
Förderung
Förderung von 2011 bis 2015
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 197350480
Each cell in the human body contains a specific set of proteins on the surface that mediate exchange and communication with the environment. Controlled turnover of individual components by endocyto-sis is particularly important for signaling proteins that regulate cell proliferation and are therefore criti-cal in cancer. Ubiquitin modification is known to trigger endocytosis by clathrin carriers and subse-quent sorting to endolysosomes for degradation. We now have evidence that another transport carrier, Caveolin-1 (Cav1) is endocytosed and sorted dependent on the ubiquitin-selective segregase Valosin-Containing Protein (VCP)/p97. VCP with its cofactor Ufd1-Npl4 is best studied in proteasomal degradation. In contrast, it cooperates with the UBXD1 cofactor to target mono-ubiquitinated Cav1 on endosomes. Consistently, VCP mutations including those that cause a degenerative disease in humans specifically block Cav1 trafficking to endolysosomes. In the proposed project, we wish to reveal the VCP-mediated molecular reaction that triggers sorting of Cav1 and understand its regulation. We then want to explore the cellular relevance of Cav1 regulation by VCP and ask whether VCP more generally controls turnover of other proteins including growth factor receptors. This work will shed light on a novel layer of ubiquitin-dependent signaling at the plasma membrane that may govern cellular homoeostasis and tumorigenesis, and will help to clarify the cellular relevance of VCP in health and disease.
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