Download Presentation

The Importance of
Understanding DUSP5 for
Angiogenesis Prevention
Brandon S Uhler, Daniel Jashinsky, Scott Beard
Marquette University, Milwaukee WI
Mentor: Dr. Ramani Ramchandran
Medical College of Wisconsin
Advisor: Dr. Daniel Sem
Marquette University
Introducing DUSP5


The DUSP5 protein plays
an important role in the
angiogenesis signaling
cascade
It contains 2 domains


The left-hand domain was
constructed via homology
modeling and binds to
another protein in the
signaling cascade
The second domain has a
phosphatase active site
which is used in
dephosphorylation
The Purpose of DUSP5
DUSP5

Phosphate
ERK
DUSP5
DUSP5 is essential in
deactivating ERK in the
Angiogenesis signaling
cascade

ERK
Continue
Signaling
Pathway to
Angiogenesis
Signaling
Cascade
ends

Phosphorylated
DUSP5
ERK

Phosphorylated ERK is
essential in continuing the
signaling cascade to
angiogenesis
DUSP5 removes the
phosphate from pERK,
terminating the cascade
If DUSP5 is not functioning
properly, angiogenesis can
continue uncontrollably
Problems with Angiogenesis



If left unaltered, the angiogenesis signaling
cascade will continue to produce blood
vessels which can lead to growths/tumors
Studies have been done on zebrafish to
analyze the relationship between DUSP5 and
uncontrolled angiogenesis
If DUSP5 is unable to carry out the
dephosphorylation of pERK, the signaling
cascade continues beyond normal vascular
development
Ligand Design


In some cases, a
mutation in the S147P
linker causes a
conformational change
in DUSP5 that hinders
proper pERK binding
Our goal was to design
ligands that inhibit this
mutation and allow for
proper binding to pERK
(1)
(2)
(3)
(4)
Ligand Design



The active site pocket on
the DUSP5 phosphatase
domain contains three
positively charged arginine
side chains
We attempted to place
negatively charged regions
in this pocket to ensure tight
binding
We also looked for other
potential binding sites in
nearby amino acids
The Next Steps



Logically, the next step in
the ligand construction
process is docking
One way to test the
inhibitory effectiveness
would be to introduce our
ligands into a vascular
system that contains both
DUSP5 and ERK
This was done in zebrafish
before, so it could be
repeated with our ligand as
a mutation inhibitor
Learning Opportunities



Clearly, DUSP5 plays an important role in
limiting harmful cell proliferation
One of the most interesting aspects of this
protein is its odd shape. The two distinct
domains offer an interesting look into the
flexing of the protein’s tertiary structure
Monitoring exactly how this conformational
change takes place would offer some insight
into how the amino acid backbone shifts and
contracts to allow proper binding to pERK.