Crislyn D

Membrane Trafficking and Signal Integration in Disease

Crislyn D'Souza-Schorey

e-mail
Professor
Ph.D., University of Texas Health Science Center at San Antonio
Postdoctoral, Washington University School of Medicine

We are interested in understanding the molecular mechanisms that underlie cell motility. Acquisition of the motile phenotype accompanies an array of cellular activities such as epithelial to mesenchymal transitions, cell migration and invasion, neuronal differentiation, phagocytosis and cell cycle progression. Our work over the past several years has documented that via its directed effects on membrane traffic and cytoskeletal remodeling, ARF6, a member of the RAS superfamily of GTPases, can impinge on a variety of cellular responses that involve rapid and progressive changes in cell shape and motility. Ongoing research avenues in the laboratory include:
 
Cell adhesion and migration in Cancer progression: The primary focus of our laboratory is to investigate how extracellular and oncogenic signals through coordinated changes in membrane traffic and the actin cytoskeleton promote the acquisition of a migratory / invasive phenotype characteristic of tumor cells. The detachment of cancer cells from the surface of a tumor, signals the beginning of a critical phase in the spread of some of the most notorious cancers – including cancers of the breast, prostate, colon and melanoma. Our approaches include the use of 3D mammary and renal epithelial cell models as well as animal models to investigate cellular changes responsible for disease initiation and progression. The 3D cell culture system allows the development of basic glandular structural units from where most cancers develop (figure 1). We are also investigating the structural and other cellular changes at the invasive front of tumor cells (figure 2). The laboratory has identified new mechanisms that result in aggressive tumor phenotypes that could serve as useful and effective platforms for diagnosis and/or cancer therapeutics.
 

Image 1 for D

Image 2 for D

Neuronal disease. We are investigating the cellular basis of pathogenesis associated with two rare neurodegenerative disorders, Huntington’s Disease (HD) and Niemann-Pick Type C (NPC). Both diseases are linked to specific genetic defects that result in misfolded proteins. Our investigations into both disorders have identified proteins of interest linked to altered vesicular trafficking that are affected by, and perhaps regulators of disease pathogenesis. 

 
Identification of ARF regulators. Although physiologically quite distinct, key cellular processes involved in tumor progression and neurodegeneration, intriguingly, require the activation of ARF proteins. Our hypothesis is that the mechanisms of regulation (i.e. activation and inactivation) and the downstream ‘targets’ of ARF are distinct in migratory/invasive tumor cells and cells undergoing degeneration. The laboratory is interested in identifying ARF regulators and effectors unique to the regulation of these distinct cellular processes. Recognition of unique regulators will provide well-positioned modalities for the use of chemical biology approaches to therapeutic targeting.
 

Selected Publications

Role for a Cindr-ARF6 axis in patterning emerging epithelia. (2011) Johnson R.I., Sedgwick A., D'Souza-Schorey, C., Cagan R.L. Mol. Biol. Cell. epub ahead of print.  doi:10.1091/mbc.E11-04-0305

ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis.  (2011) Schweitzer J.K., Sedgwick A.E., D'Souza-Schorey C.  Semin Cell Dev Biol. 22(1):39-47.  

Tushir J.S., Clancy J., Warren A., Wrobel C., Brugge J.S., D'Souza-Schorey C.  (2010) Unregulated ARF6 activation in epithelial cysts generates hyperactive signaling endosomes and disrupts morphogenesis. Mol. Biol. Cell. 21: 2355-2366.

Muralidharan-Chari V., Clancy J.W., Sedgwick, A. and D'Souza-Schorey C. (2010) Microvesicles: Mediators of extracellular communication during cancer progression. J. Cell. Sci. 123: 1603-1611. Invited Commentary.
 
Muralidharan-Chari, V., Clancy J.W., Plou C., Romao M., Chavrier P, Raposo G., and D'Souza-Schorey C. (2009) “ARF6 regulated shedding of tumor-derived plasma membrane microvesicles.” Current Biology 19(22):1875-85.
 

Muralidharan-Chari V., Hoover H., Clancy J., Schweitzer J., Suckow M., Schroeder V., Castellino F., Schorey J., D’Souza-Schorey C. (2009) ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo. Cancer Research 69: 2201-2209.

Schweitzer J., Pietrini S., D’Souza-Schorey C. (2009) ARF6-mediated endosome recycling reverses lipid accumulation defects in Niemann-Pick Type C Disease. PLoS One 4: e5193.

Sakurai-Yageta M., Recchi C., Le Dez G., Sibarita J., Daviet L., Camonis J., D’Souza-Schorey C., Chavrier P. (2008) The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA. J. Cell. Biol. 181: 985-998.

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

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.

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

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.