Kristi Grønvold Bache has defended her thesis "The function of ubiquitin-binding protein complexes in endocytic downregulation of growth factor receptors"
The results presented in the thesis represent a first step towards understanding the molecular mechanisms of endocytic downregulation of growth factor receptors and provide novel links between this pathway and growth regulation and cancer.
Visit the web page of Harald Stenmark's group to read more about the subjects covered in the thesis.
A summary from Bache Grønvold of the findings in the thesis:
The function of ubiquitin-binding protein complexes in endocytic downregulation of growth factor receptors
Ligand-induced endocytosis and lysosomal degradation of growth factor receptors have been proposed to represent an important mechanism for negative control of cell growth, and the impairment of this mechanism is believed to play a role in carcinogenesis. In the work presented here, we have characterized the machinery for sorting ubiquitinated, endocytosed cargo (including activated growth factor receptors) from early/sorting endosomes to lysosomes and showed that it is conserved from yeast to man. The hepatocyte growth factor regulated tyrosine kinase substrate (Hrs), a ubiquitin-binding protein on early endosomes, is central in this process. In complex with two other ubiquitin-binding proteins, STAM and Eps15, Hrs retains ubiquitinated cargo in clathrin-coated microdomains in the endosome membrane. Further, Hrs initiates the recruitment of an endosomal sorting complex required for transport, ESCRT-I, which acts downstream of Hrs in the sorting process. The Hrs-mediated recruitment of ESCRT-I to endosomal membranes is mechanistically similar to the recruitment of ESCRT-I to the plasma membrane of virus-infected cells, a process known to facilitate viral egress. The importance of a novel ESCRT-I subunit, hVps37A, a growth-inhibitory protein whose inactivation has been implicated in hepatocellular carcinoma, in EGFR downregulation has been established. These results represent a first step towards understanding the molecular mechanisms of endocytic downregulation of growth factor receptors and provide novel links between this pathway and growth regulation and cancer.
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