We have previously identified a signaling pathway in cancer cells, in which TβRI undergoes proteolytic cleavage in a TRAF6-dependent manner, generating TβRI-ICD which enters the nucleus when TβRI is polyubiquitinated by TRAF6 on residue K178.13, 14, 15 We also reported earlier that APPL1 interacts with TβRI-ICD via C-terminus of APPL1 and that the complex translocates to the nucleus via microtubules in a TRAF6-dependent manner.16 This evidence concerns the gene APPL1 and cancer.