Crislyn D'Souza-Schorey • Faculty • Department of Biological Sciences • College of Science • University of Notre Dame

Membrane Trafficking, Cytoskeletal Remodeling

and Signal Integration

Crislyn D'Souza-Schorey

Walther Cancer Institute Associate Professor
Ph.D., University of Texas Health Science Center at San Antonio

Postdoctoral, Washington University School of Medicine

e-mail | labpage

Well-defined changes in cell morphology accompany an array of cellular activities such as epithelial to mesenchymal transitions, cell migration and invasion, neuronal growth cone remodeling, phagocytosis and cell cycle progression. All of the above entail coordinated changes in membrane and cytoskeletal architecture. Signaling pathways that govern these processes can influence the cell's ability to undergo morphological changes in response to intracellular and extracellular signals. Proteins of the ARF and RHO families of the RAS superfamily of GTPases, via directed effects on membrane traffic and actin remodeling, can impinge on a variety of cellular responses that involve rapid and progressive changes in cell shape and motility. Research in our laboratory aims at investigating how signal transduction mediated by the ARF and RHO GTPases regulate the following cellular processes.

Cell adhesion and migration: A major focus of our laboratory is to investigate how extracellular and oncogenic signals through coordinated changes in membrane traffic and the actin cytoskeleton govern cell-cell adhesion and cell motility. Our efforts are directed at defining the signaling pathways and molecular mechanisms that underlie the acquisition of a migratory / invasive phenotype in normal and tumor cells.

Cell cycle progression: We are investigating the regulation of morphological changes which occur as cells progress through the cell cycle. Presently we are exploring the role of ARF6 and the regulation of membrane remodeling processes during cytokinesis.

Protein aggregation: We are interested in understanding the cellular processes that lead to protein aggregation in neurodegenerative disorders, such as Huntington's disease (HD). Our current goals are to elucidate the cellular machinery requisite for mutant huntingtin aggregation as well as cytoplasmic alterations that may lead to neurodegeneration in HD.

SELECTED PUBLICATIONS:

Tushir, J.S. and D'Souza-Schorey C. (2007) ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development. EMBO J. 26: 1806-1819.

D'Souza-Schorey C and Chavrier P. (2006) ARF proteins: roles in membrane traffic and beyond. Nature Reviews Mol.Cell.Biol. 7: 347-358

Lynch E.A., Stall J., Schmidt G., Chavrier P., D'Souza-Schorey C. (2006) Proteasome-mediated Degradation of Rac1-GTP during Epithelial Cell Scattering. Mol. Biol Cell. 17: 2236 -2243

Hoover, H., Muralidharan, V. D'Souza-Schorey, C. (2005) Role of the ARF6 GTPase in Tumor Cell Invasion. Methods Enzymol., 404: 134-147.

Schweitzer J., Burke, E., Goodson H., D'Souza-Schorey, C. (2005) Endocytosis resumes during late mitosis and is required for cytokinesis. J. Biol. Chem. 280: 41628-41635

D'Souza-Schorey, C. (2005) Disassembling adherens junctions: Breaking up is hard to do. Trends in Cell Biol 15: 19-26.

Palacios F., Tushir J.S., Fujita Y., and D'Souza-Schorey, C. (2005) Lysosomal targeting of E-cadherin: A unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions. Mol. Cell. Biol. 25: 389-402

Tague S., Muralidharan V., and D'Souza-Schorey C. (2004) ARF6 regulates tumor cell invasion via the activation of the MEK/ERK signaling pathway Proc. Natl. Acad. Sci. USA. 101: 9671-9676

Palacios F. and D'Souza-Schorey C. (2003) Modulation of ARF6 and Rac1 activities during epithelial cell scattering. J. Biol. Chem. 278:17395-17400.

Palacios F., Schweitzer J., Boshans R.L. and D'Souza-Schorey, C. (2002) ARF6-GTP recruits nm23-H1 to facilitate dynamin-dependent endocytosis during adherens junction disassembly Nature Cell Biology 4: 929-936.

Schwetizer J., and D'Souza-Schorey, C. (2002) Localization and activation of ARF6 during mitosis. J. Biol. Chem. 277: 27210-27216.

Peters P*., Ning K.*, Palacios F., Kazantsez A., Thompson L., Bates G., and D'Souza-Schorey C. (2002) Arfaptin 2 regulates the aggregation of mutant huntingtin. (*equal contribution) Nature Cell Biology 3:240-245

Muchowski P., Ning K., D'Souza-Schorey C., and Fields S.F (2002) Requirement of an intact microtubule cytoskeleton for aggregation of huntingtin exon 1. Proc. Natl. Acad. Sci. (USA) 99:727-732

Palacios F., Price L., Schweitzer J., Collard J., and D'Souza-Schorey, C. (2001) An essential role for ARF6-regulated membrane traffic in adherens junction assembly and epithelial cell migration. EMBO J . 20: 4973-4986

Boshans R., Szanto S., Van Aelst L., and D'Souza-Schorey C. (2000) Membrane traffic and actin remodeling: Coordinated regulation by ARF6, Rac1 and RhoA. Mol. Cell. Biol. 20: 3865-3694.

Franco M., Peters P.J., Boretto J., Van Donselaar E., D'Souza-Schorey C., and Chavrier P. (1999) EFA6, a novel exchange factor for ARF6 coordinately regulates membrane trafficking and actin organization. EMBO J. 18: 1480-1491

D'Souza-Schorey C., Van Donselaar E., Hsu V., Yang C.Z., Stahl P.D. and Peters P.J (1998) ARF6 targets recycling endosomal vesicles to the plasma membrane: Insights from an ultrastructural investigation. J. Cell. Biol. 140: 603-616.

D'Souza-Schorey C., Boettner B., and Van Aelst L (1998) Rac regulates integrin-mediated spreading and adhesion of T lymphocytes. Mol. Cell. Biol. 18: 3936 – 3946

Van Aelst L. and D'Souza-Schorey C. (1997) Rho GTPases and signaling networks. Genes and Developement 11: 2295-2322.

Li G., D'Souza-Schorey C., Barbieri M.A., Roberts R., Kipple A., Williams L.T., and Stahl P.D. (1995) Evidence for Phosphatidylinositol 3-Kinase as a regulator of endocytosis via activation of Rab 5. Proc. Natl. Acad. Sci. (USA) 92, 10207 - 10211.

D'Souza-Schorey C., Li G., Colombo M.I., and Stahl P.D. (1995) A regulatory role for ARF6 in receptor-mediated endocytosis. Science 267: 1175-1178.