HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity.

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCF?-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate ...
TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to ?-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Breast Neoplasms, Carcinogenesis, Cell Transformation, Neoplastic, Female, Humans, Intracellular Signaling Peptides and Proteins, Ligases, Phosphoproteins, Trans-Activators, Transcription Factors, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Ubiquitination, Ubiquitins, YAP-Signaling Proteins, beta-Transducin Repeat-Containing Proteins
EMBO J
Date: Feb. 15, 2023
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