More about Shawn Ellerbroek
- Curriculum Vitae (PDF)
- Student Presentations (PDF)
Director of Undergraduate Research
B.A., 1995, University of Iowa
Ph.D., 2000, Northwestern University
American Cancer Society Postdoctoral Fellow 2001-2004
CH 113 Principle of Chemistry
CH 130 Hot Topics in Science and Medicine
CH 205 Introductory Organic Chemistry
CH 325 Biochemistry
CH 425 Advanced Biochemistry
CH 455 Methods of Biochemical Research
CH 456 Student Originated Research
GM 359 Tanzania: Culture and Current Issues
ID 359 Tanzania and the Global AIDS Crisis
Ellerbroek Lab Publications:
Areas of Research Interest
I am interested in studying regulation of cell movement and invasion. My current project focuses on molecules that are believed to help regulate neurogenesis and neuron maintenance The details of our work are described below.
Alzheimer’s and Parkinson’s disease are the two most prevalent neurodegenerative disorders in the United States, affecting roughly 5.3 million and 1 million Americans, respectively (Alzheimer’s Association, 2016 and NINDS, 2015). The mechanisms of these diseases, however, are not well understood. One outstanding goal of current research is to increase our understanding of neurological disorder etiology at the molecular level.
Among potential target molecules, the Rho family of small intracellular GTPases stand out as being neuronally expressed and protein mediators of cell proliferation, protrusion, polarity, and migration (reviewed in 1-3). There are over twenty known mammalian Rho GTPases of both singular and overlapping cell functions (1). Rho GTPases become activated in cells by binding a GTP nucleotide and, as molecular switches, turn themselves “off” through their intrinsic GTPase activity (4). Upon activation, Rho GTPases adopt a conformation that permits binding of intracellular effectors molecules, including kinases and lipases, which in turn orchestrate a number of cellular events, including neurogenesis and neuronal signaling (4). Additionally, some Rho GTPases have been shown antagonize neurite formation, a process typically critical for guidance and synaptic plasticity (1).
Rho proteins can spontaneously exchange a GDP for a GTP nucleotide in order to adopt an active conformation state, but the rate of nucleotide release is too slow for the dynamic signaling demands of a cell. Rho proteins are chiefly activated through the catalytic binding activity of a group of larger intracellular molecules termed guanine nucleotide exchange factors, or “GEFs” (reviewed in 5,6). Essentially, a GEF operates by binding to a Rho protein in order to produce a nucleotide-free state. Subsequently, and in conjunction with GEF release, a Rho protein will then bind a free GTP nucleotide and thus adopt an active conformation that generates an effect within a cell. One such GEF discovered in 2002 by our faculty mentor is XPLN (eXpressed in Platelets Leukocytes and Neuronal cells, pronounced “zeppelin”) that catalyzes RhoA activation (7). Activated RhoA promotes actin polymerization and actomyosin contraction while regulating microtubule stability (reviewed in 1).
A number of GEFs have been identified as containing small motif (3-4 amino acid residues) in their carboxyl termini that bind PDZ domain containing protein (8). As XPLN is included in that group, our faculty mentor previously performed a pulldown experiment using immobilized XPLN carboxyl tail peptide or scrambled control peptide and mouse brain lysates. Using mass spec analysis of bound proteins specifically pulled down by the XPLN carboxyl tail peptide, two unique PDZ proteins were identified, PSD (postsynaptic density)-95 and Chapsyn110 (also known as PSD-93) (Figure 1). This binding has not been published and constitutes the basis of this proposal.
As their name suggest, Chapsyn110 and PSD-95 both localize to postsynaptic densities of neurons (9). Functionally, these two proteins are members of the highly conserved MAGUK family, which regulate formation, function, and plasticity of synapses (10). Chapsyn110 and PSD-95 show similar expression profiles (hippocampus, visual cortex, and spinal column), while PSD-95 is additionally found in adult brain/ cerebellum (11). As XPLN binds Chapsyn110 and PSD-95, both of which have been linked with synapse formation and maintenance, we implicate XPLN as a potential regulator of neuronal plasticity. The broader significance of this proposal lies in ability to advance our understanding of molecules implicated in a host of neurological events and pathologies, including human brain development, Alzheimer’s, Parkinson’s, and Autism Spectrum Disorders(12-14).
We are currently examining the interaction between XPLN and PSD-95 and Chapsyn-110. The proposed hypothesis is that XPLN binding to PSD-95 and/or Chapsyn-110 will alter cellular localization of these PSD proteins and/or negatively impact XPLN’s ability to activate RhoA. We plan to use a combination of biochemical and immunofluorescence assays to probe the potential functional relationship between two postsynaptic density (PSD) proteins, Chapsyn110 and PSD-95, and XPLN.
- A.J. Ridley “Rho GTPase signaling in cell migration” Curr Opin Cell Biol. 6 (2015) p.103-112.
- K. Burridge and K. Wennerberg. “Rho and Rac take center stage”. Cell 116,2 (2004) p.167-179.
- K. Wennerberg and C.J. Der, “Rho-family GTPases: It’s not only Rac and Rho (and I like it). Journal of Cell Science 117 (2004) p. 1301-1312.
- Jaffe, A.B. and A. Hall “Rho GTPases: biochemistry and biology” Annu. Rev. Cell Dev. Biol. 21 (2005) p.247–269.
- A. Schmidt, and A.Hall, A. “Guanine nucleotide exchange factors for Rho GTPases: turning on the switch” Genes Development 16 (2002) p.1587-1609.
- K. L. Rossman, C.J. Der, and J. Sondek “GEF means go: turning on Rho GTPases with guanine nucleotide exchange factors” Nature Reviews 6 (2005) p.167-180.
- W.T. Arthur, S.M. Ellerbroek, C.J. Der, K. Burridge, and K. Wennerberg “XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC” Journal of Biological Chemistry 277, 45 (2002) p.42964-42972.
- R. García-Mata and K. Burridge. “Catching a GEF by its tail” Trends Cell Biol. 17, 1 (2007) p.36-43.
- C. Aoki, I. Miko, H. Oviedo, T. Mikeladze-Dvali, L. Alexandre, N. Sweeney, and D.S. Bredt “Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex” Synapse 40, p.239–257.
- C. Oliva, P. Escobedo, C. Astorga, C. Molina, and J. Sierralta J. “Role of the MAGUK protein family in synapse formation and function” Dev Neurobiol. 72, 1 (2012) p.57-72.
- N. Sans N, R.S. Petralia, Y.X. Wang, J. Blahos II, J.W. Hell, and R.J. Wenthold RJ. “A developmental change in NMDA receptor-associated proteins at hippocampal synapses” J Neurosci 20 (2000) p.1260–1271.
- M. Costa-Mattioli and L.M. Monteggia “mTOR complexes in neurodevelopmental and neuropsychiatric disorders” Nature Neuroscience 16, (2013) p.1537-1543.
- A. Savioz, G. Leuba, and P.G. Vallet “A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer’s disease” Ageing Res Rev 18 (2014) p. 86-94.
- C. Fourie, E. Kim, H. Waldvogel, J.M. Wong, A. McGregor, R.L. Faull, and J.M. Montgomery “Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington’s Disease and Parkinson’s Disease Human Brains” Neurodegener Dis. 2014:938530