The general scientific theme in the laboratory is to define the role of accessory/scaffolding proteins (such as caveolin and EBP50/NHERF1) in the regulation of cellular and tissue functions. Our efforts focus on two specific areas:
 
1.) Role of EBP50/NHERF-1 on vascular remodeling.  The Ezrin-Radixin-Moesin Binding Phosphoprotein of 50 kDa (EBP50), also known as NHERF-1 is a PDZ domain-containing scaffolding protein. Our studies show that EBP50 is expressed at low levels in healthy vessels but is up-regulated following arterial injury. EBP50 contributes to the proliferation of vascular smooth muscle cells (VSMC). The temporal expression of EBP50 following arterial injury and its ability to regulate specific cell cycle proteins and signaling receptors suggest that this adaptor protein plays a key role in the integrated response of VSMC to injury. Current studies aim at determining the role of EBP50 on vascular remodeling.
 
Expression of PTHrP and EBP50 in restenotic carotid arteries. Sections from rat carotid arteries 2 weeks after angioplasty were fixed and immunostained for PTHrP (upper panels) or EBP50 (lower panels) (in green). Nuclei were visualized with DRAQ5 (in red). Scale bars, 50 mm.
















2.) Cellular regulation of the glucagon-like peptide 1 (GLP-1R) receptor and its role in regulating beta cell function, proliferation and survival. One of the most promising therapeutic targets for the treatment of type 2 diabetes is the glucagon-like peptide 1 receptor (GLP-1R). The well documented ability of GLP-1R agonists, either GLP-1 itself or exendin-4, to stimulate glucose-dependent insulin secretion and increase beta cell proliferation and survival led to the approval of exendin-4 for the treatment of type 2 diabetes. Our studies show that the GLP-1R interacts with caveolin-1 and this is necessary for the trafficking of the GLP-1R to the cell membrane and directs its localization to lipid rafts. The central hypothesis of this project is that the interaction between GLP-1R and caveolin-1 and its localization in lipid rafts is a fundamental mechanism controlling both the insulinotropic and the proliferative actions of GLP-1 and exendin-4.


GLP-1R and caveolin-1. HEK293 cells stably expressing GLP-1R-GFP (green) were stimulated with exendin-4. Cells were fixed, immunostained for caveolin-1 (in red), and examined by confocal fluorescence microscopy. Extensive internalization of the GLP-1R-GFP occurs and the internalized GLP-1R-GFP colocalizes with caveolin-1.

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Important Publications

Song GJ, S Barrick, KL Leslie, B Sicari, NM Fiaschi-Taesch and A Bisello.  EBP50 inhibits the anti-mitogenic action of the parathyroid hormone type 1 receptor in vascular smooth muscle cells.  J Mol Cell Cardiol 49:1012-2021, 2010.

Song GJ, N Fiaschi-Taesch and A Bisello. Endogenous parathyroid hormone-related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol Endocrinol 23:1681-1690, 2009.

Fiaschi-Taesch N, BM Sicari, K Ubriani, T Bigatel, KK Takane, I Cozar-Castellano, A Bisello, B Law and AF Stewart. Cellular mechanism through which parathyroid hormone-related protein induces proliferation in arterial smooth muscle cells: definition of an arterial smooth muscle PTHrP/p27kip1 pathway. Circ Res 99:933-942, 2006.

Syme CA, L Zhang and A Bisello. A. Caveolin-1 regulates cellular trafficking and function of the glucagon-like peptide 1 receptor. Molecular Endocrinology 20:3400-3411, 2006.

Syme CA, PA Friedman and A Bisello. Parathyroid hormone receptor trafficking contributes to the activation of extracellular signal-regulated kinases but is not required for regulation of cAMP signaling. J Biol Chem 280:11281-11288, 2005.

Bisello A, D Manen, DD Pierroz, TB Usdin, R Rizzoli and SLFerrari. Agonist-specific regulation of parathyroid hormone (PTH) receptor type 2 activity: structural and functional analysis of PTH- and tuberoinfundibular peptide (TIP) 39-stimulated desensitization and internalization. Mol Endocrinol 18:1486-1498, 2004.

Bisello A, M Chorev, M Rosenblatt, L Monticelli, DF Mierke and SL Ferrari. Selective ligand-induced stabilization of active and desensitized parathyroid hormone type 1 receptor conformations. J Biol Chem 277:38524-38530, 2002.

Ferrari SL, Behar V, Chorev M, Rosenblatt M and Bisello A. Endocytosis of ligand--human parathyroid hormone receptor 1 complexes is protein kinase C-dependent and involves ß-arrestin2: Real-time monitoring by fluorescence microscopy. J Biol Chem 274:29968-29975, 1999.