TEADs Mediate Nuclear Retention of TAZ to Promote Oncogenic Transformation

Abstract

The transcriptional coactivators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. The expression level of TAZ is recently shown to be elevated in invasive breast cancer cells and some primary breast cancers. TAZ is important for breast cancer cell migration, invasion, and tumorigenesis, but the underlying mechanism is not defined. In this study, we show that TAZ interacts with TEAD transcriptional factors. Knockdown of TEADs suppresses TAZmediated oncogenic transformation of MCF10A cells. Uncoupling TAZ from Hippo regulation by S89A mutation enhances its transforming ability. Several residues located in the N-terminal region of TAZ are identified to be important for interaction with TEADs, and these same residues are equally important for TAZ to transform MCF10A cells. Mechanistically, TAZ mutants defective in interaction with TEADs fail to accumulate in the nucleus. Live cell imaging of enhanced green fluorescent protein-TAZ and its mutant defective in TEAD interaction suggests that TEAD interaction mediates nuclear retention. These results reveal a novel mechanism for TEADs to regulate nuclear retention and thus the transforming ability of TAZ.

Structural and functional analysis of the YAP-binding domain of human TEAD2

“…Previous studies have mapped the TBD of YAP to a small N-terminal region containing residues 48-102 ( Fig. 1A) (30,31). We expressed a large fragment of YAP (residues 2-268) containing the TBD and the two WW domains, labeled it with 15 N, and acquired a 2D 1 H∕ 15 N heteronuclear single quantum correlation (HSQC) spectrum ( Fig.…”

The Hippo Tumor Pathway Promotes TAZ Degradation by Phosphorylating a Phosphodegron and Recruiting the SCFβ-TrCP E3 Ligase

“…We previously demon- strated that the Hippo pathway inhibits TAZ by promoting cytoplasmic localization via Ser-89 phosphorylation, which generates a 14-3-3 binding site (15). This provides a mechanism of spatial separation of TAZ by sequestering it away from its nuclear target transcription factors, such as TEAD (26,33). In this study we revealed another mechanism, SCF ␤-TrCP -mediated ubiquitylation and 26 S proteasome-dependent degradation, for the regulation of TAZ by the Hippo pathway via protein stability control.…”

Hippo Component TAZ Functions as a Co-repressor and Negatively Regulates ΔNp63 Transcription through TEA Domain (TEAD) Transcription Factor

“…Thus, to modulate transcription of downstream cellular genes, TAZ requires interactions with transcription factors through its TBD or WW (W, tryptophan) domain. Previous studies have shown that TAZ interacts with members of the TEAD family of transcription factors (TEAD1-4) through seven conserved residues in the TBD of TAZ (23,28). Among these, two phenylalanine residues located at positions 52 and 53 (Phe-52/53) were shown to be critical for TAZ-TEAD binding.…”