Here we show that the kinase activity of the IKK-complex is required for the activation of ErbB-2 and RhoA signalling mediated through B-family plexins in response to semaphorins, and we provide evidence that activation of IKK signalling promotes plexin-B signalling in cancer cells and osteoblasts, leading to tumour progression and bone loss, respectively. Here, RHOA is linked to cancer.