Dependence of Dbl and Dbs Transformation on MEK and NF-κB Activation

Abstract

Dbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (>20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-kappaB transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-kappaB, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-kappaB-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation.

α-Catulin, a Rho signalling component, can regulate NF-κB through binding to IKK-β, and confers resistance to apoptosis

“…Indeed, a number of studies have reported crosstalk between the RhoA signalling pathway and NF-kB (Perona et al, 1997;Montaner et al, 1998Montaner et al, , 1999Hippenstiel et al, 2002). In addition, members of the transforming protein family Dbl of Rho GEFs efficiently activate transcription from NF-kB-responsive elements (Whitehead et al, 1999), but the molecular basis for this activation remained elusive.…”

ROCK I-mediated activation of NF-κB by RhoB

“…IκB(SS) is a derivative of IκBκ that is mutated on serines 32 and 36 [30]. Since this mutant cannot be phosphorylated by the IKK complex, it binds irreversibly to NF-κB and blocks nuclear translocation.…”

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

“…Which RhoA-modulated transcription factors are involved in this process is unknown, but the presence of AP-1-and NF-B-responsive elements in the uPAR promoter points to a role of both TFs in this process (Dang et al, 1999;Wang et al, 2000). Furthermore, NF-B has also been related to Rho GTPase-induced neoplastic transformation (Whitehead et al, 1999). Recently, Marinissen et al (2001) described the role of two other transcription factors, ATF2 and MEF2A, in RhoA-mediated transformation via transcription of the c-jun gene.…”