Mattioni A, Boldt K, Auciello G, Komada M, Rappoport JZ, Ueffing M, Castagnoli L, Cesareni G, Santonico E. Ring Finger Protein 11 acts on ligand-activated EGFR via the direct interaction with the UIM region of ANKRD13 protein family. FEBS J. 2020 Aug;287(16):3526-3550. doi: 10.1111/febs.15226. Epub 2020 Feb 11. PMID: 31985874.

RING finger protein 11 (RNF11) is a highly conserved E3 ligase belonging to the Really Interesting New Gene (RING) family and is frequently overexpressed in various human tumors. Despite its established role in crucial cellular processes, the precise molecular mechanisms governing RNF11 function remain poorly understood.

Through stable isotope labeling by amino acids in culture (SILAC)-based proteomics analysis, we identified 51 proteins that co-immunoprecipitate with either wild-type RNF11 or its catalytically inactive mutant. Among these interactions, our study focused on the Ankyrin repeat domain-containing protein 13 (ANKRD13) family, which features ubiquitin-interacting motifs (UIMs) that specifically recognize Lys-63-linked ubiquitin (Ub) chains attached to the Epidermal growth factor receptor (EGFR) following ligand binding.

Our findings demonstrate that ANKRD13A, ANKRD13B, and ANKRD13D form a complex with RNF11 in vivo, with UIMs being essential for complex formation. Interestingly, unlike the conventional UIM binding mode, ubiquitin modification of RNF11 is not necessary for its interaction with ANKRD13 proteins.

Moreover, we show that the interaction between ANKRD13A and RNF11 is modulated by EGF stimulation, leading to the transient assembly of a complex comprising ANKRD13A, RNF11, and activated EGFR during the early phases of receptor endocytosis. The loss of function of E3 ligases, including Itchy E3 ubiquitin-protein ligase (ITCH) or RNF11, either abolishes or increases the ubiquitination of endogenous ANKRD13A, consequently altering its binding capacity to activated EGFR.

We propose a model in which ANKRD13 proteins serve as molecular scaffolds, facilitating the transient interaction between activated EGFR and the E3 ligases ITCH and RNF11. By modulating the ubiquitination status of ANKRD13A and, thereby, its endocytic adaptor function, RNF11 plays a critical role in sorting activated EGFR for lysosomal degradation.

This version emphasizes key scientific terms such as RNF11, E3 ligase, EGFR, ubiquitin-interacting motifs (UIMs), and lysosomal degradation, enhancing searchability and relevance for researchers.