Vitamin A Research Today is a free monthly online journal that collates and summarizes the latest research about Vitamin A, including details on retinol, benefits, dosage, supplements, deficiency, information. | ||||||||
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Retinoic acid as a modulator of the activity of protein kinase Calpha.López-Andreo MJ, Torrecillas A, Conesa-Zamora P, Corbalán-García S, Gómez-Fernández JC Departamento de Bioquímica y Biología Molecular (A), Facultad de Veterinaria, Universidad de Murcia, Apartado de Correos 4021, E-30080-Murcia, Spain. All-trans-retinoic acid (atRA) is a derivative of vitamin A and possesses antitumor activity. We demonstrate that atRA is able to modulate the activity of protein kinase C alpha (PKCalpha), which is related to tumor development. In vitro, it was found that atRA activated PKCalpha in the presence of Ca(2+) and in the absence of phosphatidylserine, although such activity is considerably inhibited in mutations affecting residues D246 and D248 and also residue N189, all of which are known to be essential for the interaction with Ca(2+) and phosphatidylserine in the C2 domain. It was concluded that atRA substitutes phosphatidylserine although with lower specific activities. However, atRA had a biphasic effect on PKCalpha activity in the presence of activating phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate, yielding activation at low concentrations but inactivation at higher ones. This second inhibitory characteristic was not shown with K209 and K211 mutations (residues located in the Lys-rich cluster in the C2 domain) in PKCalpha. This interesting effect revealed the importance of phospholipid binding at this site to ensure maximum activity for the wild-type PKCalpha. The C1 domain was not related with the atRA effect on PKCalpha. It was concluded that whereas atRA may activate PKCalpha through the Ca(2+)-phosphatidylserine-binding site of the C2 domain, it may also inhibit the activity of this enzyme when displacing the phospholipid from the Lys-rich cluster also located in the C2 domain. Published 23 August 2005 in Biochemistry, 44(34): 11353-60.
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