Myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCK alpha, formally known as CDC42BPA) is a serine/threonine kinase that can regulate actin/myosin assembly and activity. Recently, it has been shown that it possesses a functional iron responsive element (IRE) in the 3'-untranslated region (UTR) of its mRNA, suggesting that it may be involved in iron metabolism. Here we report that MRCK alpha protein expression is also regulated by iron levels; MRCK alpha colocalizes with transferrin (TO-loaded transferrin receptors (TfR), and attenuation of MRCK alpha expression by a short hairpin RNA silencing construct leads to a significant decrease in Tf-mediated iron uptake. Our results thus indicate that MRCK alpha takes part in If-iron uptake, probably via regulation of Tf-TfR endocytosis/endosome trafficking that is dependent on the cellular cytoskeleton. Regulation of the MRCK alpha activity by intracellular iron levels could thus represent another molecular feedback mechanism cells could use to finely tune iron uptake to actual needs. (C) 2010 Elsevier Inc. All rights reserved.