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. Author manuscript; available in PMC: 2019 Apr 12.
Published in final edited form as: Cancer Discov. 2016 Dec 14;7(2):202–217. doi: 10.1158/2159-8290.CD-16-0520

Figure 6. DAB2IP and RASAL2 Cooperate to Drive Distinct Aspects of Metastasis Through Ras and NF-κB.

Figure 6.

Cartoon depicting the mechanism by which RASAL2 and DAB2IP regulate invasion, EMT, and metastasis in breast cancer. DAB2IP and RASAL2 both possess catalytic RasGAP domains. Accordingly, loss of RASAL2 and DAB2IP together potently activate all three major Ras isoforms and downstream effectors (although when all Ras isoforms are expressed they appear to exert more potent effects on K- and H-Ras). Loss of RASAL2 and DAB2IP also potently activates NF-κB. NF-κB activation requires the loss of DAB2IP, which directly affects the NF-κB pathway through its period-like domain, however NF-κB activity is further enhanced by Ras pathway activation. Our studies further suggest that while Ras activation drives invasion, NF-κB is required for EMT and metastasis. We hypothesize that it is the combined and potent activation of these two important signaling pathways that underlies the aggressive and metastatic nature of luminal B breast cancers that have lost both DAB2IP and RASAL2.