Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein

Lfc and Lsc are two recently identified oncoproteins that contain a Dbl homology domain in tandem with a pleckstrin homology domain and thus share sequence similarity with a number of other growth regulatory proteins including Dbl, Tiam-1, and Lbc. We show here that Lfc and Lsc, like their closest relative Lbc, are highly specific guanine nucleotide exchange factors (GEFs) for Rho, causing a > 10-fold stimulation of [H-3]GDP dissociation from Rho and a marked stimulation of GDP-[S-35]GTP gamma s (guanosine 5'-O-(3-thiotriphosphate) exchange, All three proteins (Lbc, Lfc, and Lsc) are able to act catalytically in stimulating the guanine nucleotide exchange activity, such Chat a single molecule of each of these oncoproteins can activate a number of molecules of Rho, Neither Lfc nor ise shows any ability to stimulate GDP dissociation from other related GTP-binding proteins ouch as Rac, Cdc42, or Res, Thus Lbc, Lfc, and Lsc appear to represent a subgroup of Dbl-related proteins that function as highly specific GEFs toward Rho and can be distinguished from Dbl, Ost, and Dbs which are less specific and show GEF activity toward both Rho and Cdc42, Consistent with these results, Lbc, Lfc, and Lsc each form tight complexes with the guanine nucleotide depleted form of Rho and bind weakly to the GDP- and GTP gamma S-bound states. None of these oncoproteins are able to form complexes with Cdc42 or Ras, However, Lfc (but not Lbc nor Lsc) can bind to Rac, and this binding occurs equally well when Rac is nucleotide-depleted or is in the GDP- or GTP gamma S-bound state, These findings raise the possibility that in addition to acting directly as a GEF for BI-ro, Lfc may play other roles that influence the signaling activities of Rac and/or coordinate the activities of the Rac and Rho proteins.