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|Title:||The Phosphorylation Motif at Serine 225 Governs the Localization and Function of Sphingosine Kinase 1 in Resistance Arteries|
|Citation:||Arteriosclerosis Thrombosis and Vascular Biology, 2009; 29(11):1916-1928|
|Publisher:||Lippincott Williams & Wilkins|
|Darcy Lidington, Bernhard Friedrich Peter, Anja Meissner, Jeffrey T. Kroetsch, Stuart M. Pitson, Ulrich Pohl and Steffen-Sebastian Bolz|
|Abstract:||Objective— The purpose of this study was to characterize a phosphorylation motif at serine 225 as a molecular switch that regulates the pressure-dependent activation of sphingosine kinase 1 (Sk1) in resistance artery smooth muscle cells. Methods and Results— In isolated hamster gracilis muscle resistance arteries, pressure-dependent activation/translocation of Sk1 by ERK1/2 was critically dependent on its serine 225 phosphorylation site. Specifically, expression of Sk1S225A reduced resting and myogenic tone, resting Ca2+, pressure-induced Ca2+ elevations, and Ca2+ sensitivity. The lack of function of the Sk1S225A mutant could not be entirely overcome by forced localization to the plasma membrane via a myristoylation/palmitylation motif; the membrane anchor also significantly inhibited the function of the wild-type Sk1 enzyme. In both cases, Ca2+ sensitivity and myogenic tone were attenuated, whereas Ca2+ handling was normalized/enhanced. These discrete effects are consistent with cell surface receptor-mediated effects (Ca2+ sensitivity) and intracellular effects of S1P (Ca2+ handling). Accordingly, S1P2 receptor inhibition (1µmol/L JTE013) attenuated myogenic tone without effect on Ca2+. Conclusions— Translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and two distinct S1P pools, proposed to be intra- and extracellular, contribute to the maintenance of vascular tone. We demonstrate in hamster resistance arteries that the serine 225 phosphorylation site on sphingosine kinase 1 (Sk1) is a molecular switch for its regulatory function in smooth muscle cells. It is critical for pressure-dependent Sk1 activation/translocation and cannot be bypassed by an artificial membrane anchor.|
|Keywords:||myogenic vasoconstriction; signal transduction; transfection; ERK1/2; sphingosine-1-phosphate|
|Description:||© 2009 American Heart Association, Inc.|
|Appears in Collections:||Molecular and Biomedical Science publications|
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