Activation of RAC1 leads to an increase in the transcriptional activity of the NFκB complex (reviewed in Kotelevets and Chastre 2020). RAC1-mediated activation of NFκB signaling is implicated in colorectal tumorigenesis upon APC loss, where RAC1 is activated as a consequence of constitutively active WNT signaling (Myant et al. 2013). Both RAC1 and RAC1b, a hyperactive variant of RAC1 that is overexpressed in a subset of papillary thyroid carcinomas and associated with an unfavorable outcome, are able to induce a significant increase of NFκB transcriptional activity (Faria et al. 2017). RAC1 activated downstream of TGFB1 signaling was reported to increase the transcriptional activity of NFκB in a NAPDH oxidase (NOX)- and reactive oxygen species (ROS)-dependent manner (Tobar et al. 2010). In a rat model of diabetic retinopathy, it was reported that the NFκB complex directly bound to the RAC1 gene promoter and stimulated RAC1 transcription when the NFκB complex subunit RELA was acetylated (Kowluru et al. 2016), thus potentially creating a positive feedback loop.
A stable association of NFκB with adherens junction proteins, primarily E-cadherin (CDH1) through β-catenin (CTNNB1), was reported to reduce transcriptional activity of NFκB (Kuphal et al. 2004: melanoma cell lines were used, Solanas et al. 2008: human cancer cell lines of mesenchymal origin were used). Loss of CDH1 and cytosolic CTNNB1 in melanoma cells induces NFκB activation in a p38 MAP-dependent manner (Kuphal et al. 2004). In human cancer cell lines of mesenchymal origin, p65 (RELA) subunit of the NFκB complex co-immunoprecipitates with CDH1 and CTNNB1, and knockdown of CDH1 by siRNA leads to increased transcriptional activity of NFκB (Solanas et al. 2008). The association of NFκB with the plasma membrane in prostate carcinoma cells is increased in the presence of DLC1, a Rho GTPase activating protein (GAP) that suppresses RHOA, RHOB, and RHOC, with modest effect on CDC42 activity and no effect on RAC1 activity (Tripathi et al. 2014).
Myant, KB, Cammareri, P, McGhee, EJ, Ridgway, RA, Huels, DJ, Cordero, JB, Schwitalla, S, Kalna, G, Ogg, EL, Athineos, D, Timpson, P, Vidal, M, Murray, GI, Greten, FR, Anderson, KI, Sansom, OJ
Faria, M, Matos, P, Pereira, T, Cabrera, R, Cardoso, BA, Bugalho, MJ, Silva, AL
© 2026 Reactome
