BBS Faculty Member - Dennis Ausiello

Dennis Ausiello

Department of Medicine

Massachusetts General Hospital
Gray-Bigelow Building, 7th Floor
55 Fruit Street
Boston, MA 02114
Tel: 617-726-5660
Fax: 617-724-7441
Email: dausiello@partners.org
Lab Members: 3 postdoctoral fellows



We are interested in epithelial function involving signal transduction, membrane protein trafficking, and ion and water channel regulation using the tools of cell and molecular biology, physiology and biophysics.

The study of GPCR has grown from a classical model of membrane associated ligand-induced binding, activation and desensitization to a more complex cascade of signaling mediated both at the plasma membrane and through protein scaffolding in the intracellular environment. Using the V2R as a prototype, and using FRET, confocal, electron microscopy and real-time imaging of cultured epithelial cells, we have studied the molecular events of hormone action from ligand binding through intracellular degradation of the receptor in lysosomes.

These processes involve a large portfolio of auxiliary proteins some of which are recruited by the receptor itself, (i.e. ESCRT proteins that are potentially involved in intracellular signaling, targeting and degradation). As part of the cell biological pathway there exist parallel or sequential signaling events some mediated by the classical cAMP pathway, others mediated through scaffolding a heterogeneous group of signaling molecules including protein kinases. In concert, these signals mediate the movement of AQP water channels to and from the plasma membrane as well as orchestrate the assembly, disassembly of signaling complexes and maintain the structural integrity of the cell associated with vasopressin action. Emphasis on monomeric G proteins function has defined novel roles for both heterotrimeric and monomeric G-proteins in protein trafficking. The PT toxin sensitive G-a1pha-i3 has been shown by us to be involved in the constitutive trafficking pathway from the Golgi to the membrane. The monomeric G-protein ARF6 has been shown by us to be a key regulator of the endocytic pathway and importantly binds to the recently discovered ph-sensitive protein component of the vesicular H-ATPase.

These studies have elucidated general mechanisms of G-protein coupled signaling as well as novel characteristic of the V2R receptor, particularly by its unique pattern of intracellular trafficking and degradation. These studies have direct implications for human disease including the pathophysiology of water metabolism, such as heart failure and liver disease and the genetic disease nephrogenic diabetes insipidus.



Last Update: 8/9/2013



Publications

For a complete listing of publications click here.

 


 

Bouley R, Sun TX, Chenard M, McLaughlin M, McKee M, Lin HY, Brown D, Ausiello DA. Functional role of the NPxxY motif in internalization of the type 2 vasopressin receptor in LLC-PK1 cells. Am J Physiol Cell Physiol. 2003 Oct;285(4):C750-62.

Bouley R, Lin HY, Raychowdhury MK, Marshansky V, Brown D, Ausiello DA. Downregulation of the vasopressin type 2 receptor (V2R) after vasopressin-induced internalization: involvement of a lysosomal degradation pathway. Am J Physiol Cell Physiol. 2005 288: C1390-C1401.

Hurtado-Lorenzo A, Skinner M, El Annan J, Futai M, Sun-Wada GH, Bourgoin S, Casanova J, Wildeman A, Bechoua S, Ausiello DA, Brown D, Marshansky V. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol. 2006 Feb;8(2):124-36.

Bouley, R., Hawthorne, G., Russo, L., Ausiello, D. A., and Brown, D. Aquaporin 2 (AQP2) and vasopressin receptor (V2R) endocytosis in kidney epithelial cells: AQP2 is located in “endocytosis-resistant” membrane domains after vasopressin treatment. Biol. Cell. 2006 Apr;98(4):215-32.



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