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Lorraine
Santy
Associate Professor of Biochemistry and Molecular Biology
Lorraine Santy

Department of University Committees

  • BMB Ombuds

  • BMMB Steering Committee

  • MCIBS Steering Committee

  • BMB/MICRB Honors Advisor

 

Program of Departmental Affiliations

The BMMB Graduate Program The Molecular, Cellular, and Integrative Biosciences Program

 

Centers

Center for Cellular Dynamics

 

Research Summary

Epithelial cells form barriers that divide different compartments in the body.  Epithelial cells include the cells lining the intestine, lungs, kidney tubules, and milk ducts.  These cells are normally stationary but become migratory during processes such as the repair of tissue damage or the metastasis of epithelial tumors.  The Santy lab is interested in understanding the signals and processes that initiate migration in epithelial cells and the role of epithelial migration in both normal function and disease. 

Epithelial Cells

Cytohesin/Arf signaling in HGF stimulated epithelial migration

The development of motility involves large changes in the architecture and behavior of these cells.  We are focused on mapping out signals that remodel the cell and kick off epithelial migration. HGF (hepatocyte growth factor) is a small protein that potently stimulates migration in a wide variety of epithelial cells.  HGF is upregulated in response to tissue damage and enhanced HGF signaling is correlated with metastatic development in a number of cancers.  Members of the Arf family of small GTPases are protein switches that control membrane remodeling and signaling events.  Enhanced expression of the Arf-activating cytohesin proteins in epithelial cells mimics the treatment of these cells with HGF.  Furthermore blocking cytohesin or Arf function prevents HGF from stimulating epithelial migration. We have found that cytohesin/Arf signaling promotes the activation of Rac, a protein that directly stimulates the remodeling of cell shape.  Several projects in the lab are focused on understanding how HGF stimulates cytohesin activity and how cytohesin/Arf activation promotes the activation of Rac.

 

Cytohesin/Arf regulation of adhesion receptor recycling

Adhesion receptors create spots where cells are anchored down to the underlying extracellular matrix.  These attachments provide traction points that the cells pull against while migrating.  During migration old receptor complexes are internalized and recycled to make new attachment spots.  We have found that cytohesin-2 is required for the recycling of these receptors to the cell surface.  We are investigating the signals that stimulate cytohesin-2 to promote the formation of new adhesion receptor complexes.

 

Cytohesin splice variant functions

The cytohesins are each made in two different versions by alternative splicing.  We have found that one of these splice variants is required for adhesion receptor recycling while the other plays no role in this process.  These splice variants differ in their lipid binding specificity.  We are investigating the unique roles of these different splice variants.

 

Recovery from acute kidney injury

Acute Kidney Injury (AKI) is a serious complication in hospitalized patients, particularly for patients in intensive care.  Production of both HGF and the HGF receptor is upregulated in the injured kidney.  HGF stimulates the kidney epithelial cells that survived the initial insult to migrate and repopulate the kidney tubules.  We are using an in vivo model of AKI to investigate the involvement of cytohesins in this process.  Furthermore we are testing if we can use what we have learned about stimulating cytohesin activity to promote recovery from AKI.

 

 

Honors and Awards

  • 2013 Daniel R. Tershak Memorial Teaching Award

 

 

Selected Publications

  • Sztul, E., P. W. Chen, J. E. Casanova, J. Cherfils, J. B. Decks, D. G. Lambright, F. J. S. Lee, P. A. Randazzo, L. C. Santy, A. Schurmann, I. Wilhelmi, M. E. Yohe and R. A. Kahn (2019). "ARF GTPases and their GEFs and GAPs: concepts and challenges." Molecular Biology of the Cell 30(11): 1249-1271.
     
  • Koubek, E. J. and L. C. Santy (2018). "ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation." Small GTPases 9(3): 242-259. 
     
  • Salem, J. C., M. M. Reviriego-Mendoza and L. C. Santy (2015). "ARF-GEF cytohesin-2/ARNO regulates R-Ras and alpha5-integrin recycling through an EHD1-positive compartment." Mol Biol Cell 26(23): 4265-4279. 
     
  • Reviriego-Mendoza, M. M. and L. C. Santy (2015). "The cytohesin guanosine exchange factors (GEFs) are required to promote HGF-mediated renal recovery after acute kidney injury (AKI) in mice." Physiol Rep 3(6): e12442. 
     
  • Hiester, K. G. and L. C. Santy (2013). "The cytohesin coiled-coil domain interacts with threonine 276 to control membrane association." PLoS One 8(11): e82084. 
     
  • Attar, M. A., J. C. Salem, H. S. Pursel and L. C. Santy (2012). "CNK3 and IPCEF1 produce a single protein that is required for HGF dependent Arf6 activation and migration." Exp Cell Res 318(3): 228-237.
     
  • Oh, S. J. and L. C. Santy (2012). "Phosphoinositide specificity determines which cytohesins regulate beta1 integrin recycling." J Cell Sci 125(Pt 13): 3195-3201. 
     
  • Santy, L. C., K. S. Ravichandran and J. E. Casanova (2005). "The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1." Curr Biol 15(19): 1749-1754. 
     
  • Santy, L. C. and J. E. Casanova (2001). "Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D." J Cell Biol 154(3): 599-610.