Fig. 1

Ubiquitination on RAS-RAF-MEK signal. Upon EGF or other growth factors stimulation, activated Ras-GTP enhances the transcripts of NEDD4–1 which promotes the ubiquitination on all three forms of Ras-GTP and PTEN for the proteasome degradation to accelerate the downstream signaling activation. Rabex, to some extent as a ‘break’, can ligate mono- or poly-ubiquitin (K63-link) to HRas or NRas, but not KRas, which promotes their endosome localization and lysosome degradation, thereby limiting the transformation of Ras-GTP from Ras-GDP to suppress the phosphorylation activation of ERK. Likewise, BRAF and CRAF can be ubiquitinated by RNF149 and CHIP, respectively, and be degraded by the proteasome to decelerate MEK/ERK activation, which attenuates the increase in cell growth. Following EGF stimulation, RING domain E3 ubiquitin ligases c-Cbl or Cbl-b, with the assistance of Grb2, induces mono- or poly-ubiquitination (K63-link) of EGFR and mediates the endosomal sorting and trafficking events, in which process the mono-ubiquitinated EGFR is trapped within ILVs of multivesicular bodies (MVBs), whereas poly-ubiquitinated forms remaining in the MVBs are deubiquitinated by DUB enzymes USP8, USP2a or AMSH to escape the ILVs trapping and lysosome degradation. Instead, the non-ubiquitinated EGFR forms are recycled to the cell membrane for the downstream signal activation