WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ

Abstract

The transcriptional co-activators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. YAP and TAZ both possess WW domains, which are important protein–protein interaction modules that mediate interaction with proline-rich motifs, most commonly PPXY. The WW domains of YAP have complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific manner. In this study, we show that the WW domain of TAZ is important for it to transform both MCF10A and NIH3T3 cells and to activate transcription of ITGB2 but not CTGF, as introducing point mutations into the WW domain of TAZ (WWm) abolished its transforming and transcription-promoting ability. Using a proteomic approach, we discovered potential regulatory proteins that interact with TAZ WW domain and identified Wbp2. The interaction of Wbp2 with TAZ is dependent on the WW domain of TAZ and the PPXY-containing C-terminal region of Wbp2. Knockdown of endogenous Wbp2 suppresses, whereas overexpression of Wbp2 enhances, TAZ-driven transformation. Forced interaction of WWm with Wbp2 by direct C-terminal fusion of full-length Wbp2 or its TAZ-interacting C-terminal domain restored the transforming and transcription-promoting ability of TAZ. These results suggest that the WW domain-mediated interaction with Wbp2 promotes the transforming ability of TAZ.

Defining the Protein–Protein Interaction Network of the Human Hippo Pathway

“…S3A). Cluster 1 validated previously reported interactions for YAP1 or TAZ, which include PPP1CA (51), WBP2 (52), and TP53BP2 (53). Several uncharacterized preys in this cluster, such as CCDC85C and C9orf140, were considered as potential regulators of YAP1 or TAZ.…”

The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCFβ-TrCP-dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

“…TAZ overexpression can induce epithelial cells to undergo EMT, which is associated with tumor metastasis. Moreover, TAZ expression induces oncogenic transformation in NIH3T3 cells in vitro (37). It has been reported that TAZ protein levels are elevated in human cancers (15).…”

Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador–Warts–Hippo pathway

“…To identify candidate transcriptional regulatory proteins that interact with the WW domains of Yki and its mammalian homologues, YAP and TAZ, we performed large-scale immunoprecipitations with TAZ in cultured cells. 24 A major interaction partner of TAZ was WBP2, homologues of which are found in many different species including D. melanogaster, which has a sole WBP2 homologue, CG11009 (hereafter referred to as Wbp2). The wbp2 gene is predicted to encode for two polypeptides of 337 and 427 amino acids, each of which contains a GRAM (glucosyltransferases, Rab-like GTPase activators and myotubularins) domain that has no defined function and two evolutionarily conserved P-P-X-Y (PY) motifs ( Figure 1A).…”

“…24 This analysis revealed a specific interaction with WW domainbinding protein-2 (WBP2). Interestingly, WBP2 was one of the first identified YAP-interacting proteins 25 and was previously shown to cooperate with YAP to increase ligand-dependent transactivation of oestrogen and progesterone receptors.…”