Our group is interested in mechanisms for physiological responses to nitric oxide (NO). Although NO may act directly on cells to elicit responses, other important effects of NO are mediated by S-nitrosothiols derived by the reaction of NO derivatives and cysteine thiols. Recently we have found that the amino acid transporters, LAT1 and LAT2, transport S-nitroso-L-cysteine into cells. This mechanism provides a specific and selective pathway for movement NO-bioactivity into cells. Once inside the cell, S-nitroso-L-cysteine initiates signaling by modifying critical thiols in target proteins. Among many possibilities, modification of protein tyrosine phosphatases, kinases, and GTP binding proteins may be especially important. Recent work in our lab has shown that protein tyrosine phosphatase-1b (PTP-1b) is modified by NO leading to inhibition and hyperphosphorylation of growth factor receptors. Importantly, inhibition is rapidly reversible by cellular redox systems so that NO-mediated protein thiol oxidation and subsequent reduction represents an 'on/off' mechanism for cell signaling. Current work includes studies designed to define specific physiological responses where LAT1 and LAT2 are critical.

Buckley, BJ, ZM Marshall and AR Whorton. Nitric oxide stimulated Nrf2 nuclear translocation in vascular endothelium. Biochem. Biophys. Res. Communic. 307(4): 973-979, 2003.

Suliman, HB, MS Carraway, KE Welty-Wolf, AR Whorton, and CA Piantadosi, Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1. J. Biol. Chem. 278: 41510-41518, 2003.

Brar SS, Grigg C, Wilson KS, Holder WD Jr, Dreau D, Austin C, Foster M, Ghio AJ, Whorton AR, Stowell GW, Whittall LB, Whittle RR, White DP, Kennedy TP. Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol Cancer Ther. 3(9):1049-60, 2004.

Li, Sheng, and AR Whorton, Identification of stereoselective transporters for S-nitroso-L-cysteine: Role of LAT1 and LAT2 in biological activity of S-nitrosothiols. J. Biol. Chem. 280: 20102-20110, 2005

Yu, Chang-Xi, Sheng Li, and AR Whorton. Redox regulation of PTEN by S-nitrosothiols. Molec. Pharmacol. 68(3): 847-854, 2005.

Li, Sheng and AR Whorton. Functional characterization of two S-nitroso-L-cysteine transporters which mediate movement of NO equivalents from S-nitrosoalbumin into vascular cells. Am. J. Physiol. In press, 2006.