Camilla Raiborg has defended her thesis "Hrs makes receptors silent. A key to endosomal protein sorting"
The disputation took place March 15th in the Auditorium at the Norwegian Radium Hospital.
The evaluation committee was very impressed by the quality of the work and
the candidate's performance at the disputation. The following remarks are taken from the conclusion from their statement about the thesis:
"The Dissertation focuses on a central theme in cell biology, the sorting of endocytosed proteins. The common denominator in the thesis is the Hrs and during the project several components were shown to cooperate with Hrs in the sorting process: clathrin, STAM, Eps15, AIP4 etc. The work is well planned and the methods used are excellent and always up-to-date and adapted to the problems investigated. The results presented in the five articles give novel, solid and detailed information about molecular mechanisms involved in sorting and targeting of endocytosed proteins. The dissertation is a major contribution to novel insight into receptor-downregulation. "
Read the complete statement from the evaluation committe here
Visit the web page of Harald Stenmark's group to read more about the subjects covered in the thesis.
A summary from Camilla Raiborg of the findings in the thesis:
Hrs makes receptors silent. A key to endosomal protein sorting
The human body make use of several control mechanisms to prevent cancer. This thesis-work reveals detailed molecular insight into one of these processes, receptor down-regulation. After a growth factor receptor has received a growth stimulatory signal, the activated receptor and its ligand are taken up into cells by endocytosis and transported via endosomes to lysosomes for degradation (Figure 1). The activated growth factor receptors that are destined for degradation are labelled with a molecular tag, ubiquitin. By degrading the receptor and its growth factor, the cell can assure that the receptor is silenced. This is important to prevent uncontrolled signalling. In contrast to activated growth factor receptors, endocytosed nutrient receptors are recycled back to the cell surface for reuse. The fate of the receptors is settled at the level of early endosomes, which act as the main sorting stations in the endocytic pathway. A longstanding question in the field has been how the cell is able to sort the receptors in different directions from the endosome.
The hepatocyte growth factor regulated tyrosine kinase substrate, Hrs, is a protein that is localised to the cytosolic face of early endosomes. During the project period (1999 -2004), we have defined the domains of Hrs that are responsible for its endosomal targeting. Further, we have identified a functional clathrin-binding domain in Hrs and found that Hrs is responsible for the recruitment of this coat protein to endosomes. Moreover, we have shown that Hrs - which acts in an endosomal protein complex - can bind to ubiquitin, and functions in the sorting of ubiquitinated membrane proteins into clathrin coated microdomains on endosomes. This seems to be a crucial step in the targeting of activated receptors for degradation in lysosomes and cells depleted of Hrs do not degrade the receptors properly. Thus, Hrs makes receptors silent. These findings provide novel insight into the molecular mechanisms of receptor down-regulation. By recognising ubiquitinated growth factor receptors, recruiting a clathrin coat and engaging other players in the sorting machinery, Hrs serves as a key to endosomal protein sorting.
The hepatocyte growth factor regulated tyrosine kinase substrate, Hrs, is a protein that is localised to the cytosolic face of early endosomes. During the project period (1999 -2004), we have defined the domains of Hrs that are responsible for its endosomal targeting. Further, we have identified a functional clathrin-binding domain in Hrs and found that Hrs is responsible for the recruitment of this coat protein to endosomes. Moreover, we have shown that Hrs - which acts in an endosomal protein complex - can bind to ubiquitin, and functions in the sorting of ubiquitinated membrane proteins into clathrin coated microdomains on endosomes. This seems to be a crucial step in the targeting of activated receptors for degradation in lysosomes and cells depleted of Hrs do not degrade the receptors properly. Thus, Hrs makes receptors silent. These findings provide novel insight into the molecular mechanisms of receptor down-regulation. By recognising ubiquitinated growth factor receptors, recruiting a clathrin coat and engaging other players in the sorting machinery, Hrs serves as a key to endosomal protein sorting.
Figure 1. Model for the role of Hrs in endocytic down-regulation of ubiquitinated membrane proteins. Growth factor receptors become ubiquitinated upon ligand binding and are thus routed to lysosomes via the Hrs pathway. In contrast, nutrient receptors are not ubiquitinated and therefore do not accumulate within the Hrs-containing endosomal microdomains, enabling them to recycle to the plasma mebrane.
(clathrin in red, HRS in blue, ubiquitin in yellow)
(clathrin in red, HRS in blue, ubiquitin in yellow)
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