TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins

Abstract

The highly conserved and ubiquitously expressed 14‐3‐3 proteins regulate differentiation, cell cycle progression and apoptosis by binding intracellular phosphoproteins involved in signal transduction. By screening in vitro translated cDNA pools for the ability to bind 14‐3‐3, we identified a novel transcriptional co‐activator, TAZ (transcriptional co‐activator with PDZ‐binding motif) as a 14‐3‐3‐binding molecule. TAZ shares homology with Yes‐associated protein (YAP), contains a WW domain and functions as a transcriptional co‐activator by binding to the PPXY motif present on transcription factors. 14‐3‐3 binding requires TAZ phosphorylation on a single serine residue, resulting in the inhibition of TAZ transcriptional co‐activation through 14‐3‐3‐mediated nuclear export. The C‐terminus of TAZ contains a highly conserved PDZ‐binding motif that localizes TAZ into discrete nuclear foci and is essential for TAZ‐stimulated gene transcription. TAZ uses this same motif to bind the PDZ domain‐containing protein NHERF‐2, a molecule that tethers plasma membrane ion channels and receptors to cytoskeletal actin. TAZ may link events at the plasma membrane and cytoskeleton to nuclear transcription in a manner that can be regulated by 14‐3‐3.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

“…14 Dysregulation of the Hippo pathway is correlated with epithelial to mesenchymal transition and cancer development, mainly driven by TAZ and YAP. 15 These two DNA-binding proteins are normally repressed by Mst2 and Lats2 phosphorylation, 16,17 or they are regulated by the expression and location of the cell polarity protein Scribble. 18 TAZ/YAP and epithelial to mesenchymal transition are thought to maintain a bidirectional relationship, whereby the loss of polarity and cell contacts (key events during the epithelial to mesenchymal transition process) induces the activation of both factors, which in turn participate in the epithelial to mesenchymal transition program.…”

The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members

“…Class 1: interacting proteins with co-activation function [p160 steroid hormone receptor co-activators and YAP65 (Yes-associated protein 65 kDa)]. These TEF-1 co-factors contain transactivation domains, interact with TEF-1 and activate transcription of MCATdependent promoters ( [22][23][24], and see below). Class 2: interacting proteins without co-activation function [TONDU (Vgl-1, Vestigial-like protein-1), Vgl-2 and Vgl-3].…”

“…YAP65 is approx. 45 % identical with the PDZ-binding protein TAZ (transcriptional co-activator with PDZ-binding motif) [23]. YAP65 and TAZ also have similar domain structures; one or two WW domains, a 14-3-3-binding site and a C-terminal PDZ-binding motif [23].…”

“…45 % identical with the PDZ-binding protein TAZ (transcriptional co-activator with PDZ-binding motif) [23]. YAP65 and TAZ also have similar domain structures; one or two WW domains, a 14-3-3-binding site and a C-terminal PDZ-binding motif [23]. Phosphorylated YAP65 and TAZ are bound to the phospho-serine/threoninebinding protein 14-3-3 in the cytoplasm, and dephosphorylated YAP65 and TAZ are found in the nucleus, where they function as transcriptional co-activators [23,24].…”

“…YAP65 and TAZ also have similar domain structures; one or two WW domains, a 14-3-3-binding site and a C-terminal PDZ-binding motif [23]. Phosphorylated YAP65 and TAZ are bound to the phospho-serine/threoninebinding protein 14-3-3 in the cytoplasm, and dephosphorylated YAP65 and TAZ are found in the nucleus, where they function as transcriptional co-activators [23,24]. Intracellular localization of YAP65 can be regulated by overexpression of Akt/protein kinase B [35].…”