Disabled-1 (Dab I) is a cytosolic adaptor protein that plays critical roles in cortical development. However, a detailed mechanism of action has not yet been clearly defined. Through yeast two-hybrid screening, we observed that mouse Siah-1A, an E3 ubiquitin ligase containing a RING finger motif, interacts with Dab I. Co-immunoprecipitation experiments and in vitro binding experiments both indicated direct interaction between Siah and Dab I. Steady-state expression of Siah was enhanced by the presence of Dab I or lactacystin, a representative proteasomal inhibitor. Auto-ubiquitination of Siah was inhibited by the presence of Dabl, suggesting inhibition of Siah activity and subsequent increase of Siah expression by Dabl. Both Dab1-induced increase of steady-state expression of Deleted in cololectal cancer (DCC), one of the well-known substrates of Siah, and its inhibition by SiahDeltaR suggest that Dabl increases expression of DCC through inhibiting the activity of endogenous Siah. Our results suggest that Dabl inhibits the activity of Siah. (C) 2003 Elsevier Science (USA). All rights reserved.