BBB seminar: Linda Hicke
Roles of ubiquitin in regulating receptor endocytosis
Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL, USA
Post-translational modifications control cargo sorting and assembly of sorting machinery at multiple stages of the endocytic pathway. The 76 amino acid polypeptide ubiquitin can serve as a signal to sort integral membrane proteins into budding vesicles at the plasma membrane and at endosomal compartments. In addition, monoubiquitination regulates the activity of key components of the endocytic machinery by as yet unknown mechanisms.
The role of monoubiquitin in regulating receptor endocytosis is likely to be carried out through monoubiquitin-binding proteins known as ubiquitin receptors. A variety of ubiquitin-binding domains, including the UBA, UIM, CUE, VHS and GAT motifs, are found in endocytic proteins and bind to monoubiquitin with relatively low affinity. In addition to binding ubiquitin, many, if not all, of these domains are required for monoubiquitination of the proteins within which they are carried. Monoubiquitin-binding proteins that are also monoubiquitinated are found throughout the endocytic pathway. For example, epsins, Eps15/Ede1, endophilin/Rvs167 and CIN85/Sla1 act at the plasma membrane, Rabex/Vps9 acts at an early endosomal compartment and Hrs/Vps27 and STAM/Hse1 function later in the pathway. Some of these proteins carry new monoubiquitin-binding domains that are being defined and characterized. The growing number of these proteins and the importance of ubiquitination of the endocytic machinery suggest that, whereas some of these proteins may bind to ubiquitin sorting signals on cargo proteins, ubiquitination also regulates the dynamic, regulated assembly of protein complexes required for endocytic transport.
Host: Anne.Døskeland, Department for Biomedicine
Professor Linda Hicke is one of the leading scientists in the field of the ubiquitination of proteins and the functional effect of this post-translational modification. Ubiquitination is known to play a role in protein degradation, signal transduction, receptor modulation, transcription, immune response, cell cycle, DNA repair, etc. Linda Hicke has especially explored the dynamics of the cell membrane. She studied the role played by ubiquitination in receptor down-regulation which often occurs by internalization of the receptor from the cell surface into the endocytotic pathway. She has demonstrated that the modification of receptors with the polypeptide ubiquitin serves as one type of ligand-activated internalization signal.
Linda Hicke has a long list of publications and her last paper "Ubiquitin-binding domain" is now in press in Nature Reviews Molecular Cell Biology. In 2000 she received the "Women in Cell Biology Career Recognition Junior Award" from the American Society of Cell Biology.