fig4

Figure 4. The ubiquitination-deubiquitination axis controls EGFR endocytic sorting, degradation, and recycling. Ligand-activated EGFR is ubiquitinated at specific lysine residues by E3 ligases such as CBL and ZNRF1. This ubiquitin tag is recognized by endocytic machinery (e.g., Hrs, UBE4B) and the ESCRT complex, sorting EGFR into intraluminal vesicles of MVBs for ultimate lysosomal degradation and signal termination. The process is dynamically opposed by DUBs such as USP8 and USP54, which stabilize EGFR and can promote its recycling to the plasma membrane for signal reactivation. Conversely, USP25 and HUWE1 (with the help of JMJD5) can promote the degradation of EGFR. EGFR: Epidermal growth factor receptor; CBL: Casitas B-lineage lymphoma proto-oncogene; ZNRF1: Zinc and Ring Finger 1; Hrs: hepatocyte growth factor-regulated tyrosine kinase substrate; UBE4B: Ubiquitination Factor E4B; ESCRT: endosomal sorting complex required for transport; MVBs: multivesicular bodies; DUBs: deubiquitinating enzymes; USP: Ubiquitin-Specific Peptidase; HUWE1: HECT, UBA and WWE Domain Containing E3 Ubiquitin Protein Ligase 1; JMJD5: Jumonji Domain Containing 5; SFN: Stratifin.