Faculty
Linda Hicke, PhD
Professor
Biochemistry, Molecular Biology and Cell Biology
PhD, University of California, Berkeley
Email: l-hicke@northwestern.edu
Phone: (847) 467-4490
Fax: (847) 491-4970
Room: Pancoe Rm 3401
Research Interests
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.
Selected Publications
Regulation of the RSP5 ubiquitin ligase by an intrinsic ubiquitin-binding site. French ME, Kretzmann BR, Hicke L. J Biol Chem. 2009 May 1;284(18):12071-9. Epub 2009 Feb 27.
A C-terminal sequence in the guanine nucleotide exchange factor Sec7 mediates Golgi association and interaction with the Rsp5 ubiquitin ligase. Dehring DA, Adler AS, Hosseini A, Hicke L. J Biol Chem. 2008 Dec 5;283(49):34188-96. Epub 2008 Oct 2.
Stamenova, S.D., He, Y., French, M., Francis, S.A., Kramer,
Z.B. and L. Hicke.
(2007). Ubiquitin binds to
and regulates a subset of SH3 domains. Mol. Cell.
25, 273-84.
Hicke, L., Schubert, H.L. and C.P. Hill. (2005) Ubiquitin-binding domains. Nat.
Rev. Mol.
Cell Biol. 6, 610-621.
View all publications by Linda Hicke listed in the National Library of Medicine (PubMed). IBiS students in blue