# The E3 ubiquitin ligase TRIM56 promotes aggregation and activation of Src protein through Lys63-linked polyubiquitination in hepatocellular carcinoma

## TL;DR

This study shows that TRIM56, an E3 ubiquitin ligase, promotes liver cancer by activating the Src protein through a specific type of ubiquitination.

## Contribution

TRIM56 is identified as a novel regulator of Src activation via Lys63-linked polyubiquitination in hepatocellular carcinoma.

## Key findings

- TRIM56 interacts with and catalyzes the polyubiquitination of Src at Lys184.
- TRIM56-induced Src aggregation leads to its activation and promotes HCC progression.
- TRIM56 acts as a tumor promoter and may be a therapeutic target in HCC.

## Abstract

Elevated activity of proto-oncogene tyrosine kinase Src is associated with tumorigenesis and progression of hepatocellular carcinoma (HCC). It is well recognized that activation of Src is mainly driven by its intermolecular autophosphorylation. However, the precise mechanism involved in the activation of Src remains to be fully understood. Here we identified tripartite motif-containing protein (TRIM) 56, a member of E3 ubiquitin ligase family, as a novel regulator of Src activation. The data revealed that TRIM56 directly interacted with Src and catalyzed the polyubiquitination and subsequent aggregation of Src, resulting in Src activation and HCC progression. Mechanistically, TRIM56 interacted with the SH3 domain of Src protein via its B-box1 domain and catalyzed the Lys63-linked polyubiquitination of Src at the Lys184 residue, leading to the aggregation and activation of Src. Altogether, here we demonstrated that TRIM56 acted as a tumor promoter in HCC and it exerted a novel regulatory effect on Src activation. Thus, this study suggested a promising therapeutic strategy for HCC patients by targeting TRIM56.