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Ubiquitin
is a compact yet remarkable protein that has the unusual ability
to become covalently attached to other macromolecules. This
reaction, known as ubiquitination, is catalyzed and controlled by
ubiquitin ligases, and its result is to modify the molecular landscape
of a substrate. Although ubiquitination sometimes targets proteins
for degradation by the proteasome, ubiquitin also regulates protein
activity and location by other mechanisms that are fundamentally
important, but not well-characterized. One example in which ubiquitin and ubiquitin ligases play a critical role in a proteasome-independent manner is in control of the internalization and sorting of proteins in the endocytic pathway. Dysfunction of ubiquitin-dependent endocytosis results in or is linked to many diseases, including inflammation and hypertension, as well as immune diseases, multiple cancers and viral infections. Ubiquitin-dependent endocytosis is also essential for developmental processes in complex organisms, such as cell fate specification and development of the nervous system. Specific proteins that are known to be ubiquitinated and regulated by ubiquitin-dependent endocytosis include leptin receptors, growth factor receptors, glucose transporters, glutamate receptors and ion channels. One of the roles of ubiquitin in receptor internalization is to serve as an internalization signal appended to the receptor itself; another role is to modify and regulate components of the endocytic machinery. Several endocytic machinery proteins are modified with monoubiquitin. Surprisingly, many of these monoubiquitinated endocytic proteins also bind to ubiquitin noncovalently through ubiquitin-binding domains (UBDs). We have used the advantageous combination of genetics, molecular biology and biochemistry in the yeast Saccharomyces cerevisiae to identify endocytic proteins that bind to ubiquitin or to a regulatory ubiquitin ligase. Based on our studies with these proteins, we hypothesize that the ubiquitin ligase and ubiquitin-UBD interactions regulate the assembly of the endocytic machinery into dynamic protein networks at sites of endocytosis on the plasma membrane. The specific mechanisms by which ubiquitin acts to facilitate and regulate endocytosis are not yet known, and are the targets of our current investigation. Because UBDs are found in many proteins with diverse functions, the regulation of protein complex assembly by ubiquitin-UBD interactions is also likely to occur in other basic cell biological processes. Our long-term goal is to understand how protein trafficking pathways are regulated by ubiquitin and to apply this knowledge to other cellular processes. |
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Terrell, J., Shih, S., Dunn, R. and L. Hicke. (1998).
A function for Shih, S.C., Sloper-Mould, K.E. and L. Hicke. (2000).
Monoubiquitin carries a deHart, A.K.A., Schnell, J.D., Allen, D.A. and L. Hicke. (2002).
The conserved Shih, S.C., Katzmann, D.J., Schnell, J.D., Emr, S.D.
and L. Hicke. (2002). Shih, S.C., Prag, G., Francis, S.A., Sutanto, M.,
Hurley, J.H. and L. Hicke. (2003). Hicke, L. and R. Dunn. (2003). Regulation of membrane
protein transport by Dunn, R.D., Klos, D.A., Adler, A.S. and L. Hicke.
(2004). The C2 domain of the Hicke, L., Schubert, H.L. and C.P. Hill.
(2005) Ubiquitin-binding domains. Nat. Stamenova, S.D., He, Y., French, M., Francis, S.A., Kramer,
Z.B. and L. Hicke. |
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View all publications by publications by Linda Hicke listed in the National Library of Medicine (PubMed). |
