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Title: Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway

Authors:
; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. UTSMC
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
DODNIHOTHER
OSTI Identifier:
1248393
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Chemical Biology; Journal Volume: 12
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, Wu, Xu, Harvard-Med), Jilin), and JHU-MED). Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. United States: N. p., 2016. Web. doi:10.1038/nchembio.2036.
Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, Wu, Xu, Harvard-Med), Jilin), & JHU-MED). Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. United States. doi:10.1038/nchembio.2036.
Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, Wu, Xu, Harvard-Med), Jilin), and JHU-MED). Fri . "Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway". United States. doi:10.1038/nchembio.2036.
@article{osti_1248393,
title = {Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway},
author = {Chan, PuiYee and Han, Xiao and Zheng, Baohui and DeRan, Michael and Yu, Jianzhong and Jarugumilli, Gopala K. and Deng, Hua and Pan, Duojia and Luo, Xuelian and Wu, Xu and Harvard-Med) and Jilin) and JHU-MED)},
abstractNote = {},
doi = {10.1038/nchembio.2036},
journal = {Nature Chemical Biology},
number = ,
volume = 12,
place = {United States},
year = {Fri Jul 08 00:00:00 EDT 2016},
month = {Fri Jul 08 00:00:00 EDT 2016}
}
  • The heterodimeric structure of the MST1 and RASSF5 SARAH domains is presented. A comparison of homodimeric and heterodimeric interactions provides a structural basis for the preferential association of the SARAH heterodimer. Despite recent progress in research on the Hippo signalling pathway, the structural information available in this area is extremely limited. Intriguingly, the homodimeric and heterodimeric interactions of mammalian sterile 20-like (MST) kinases through the so-called ‘SARAH’ (SAV/RASSF/HPO) domains play a critical role in cellular homeostasis, dictating the fate of the cell regarding cell proliferation or apoptosis. To understand the mechanism of the heterodimerization of SARAH domains, the three-dimensional structuresmore » of an MST1–RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography and were analysed together with that previously determined for the MST1 SARAH homodimer. While the structure of the MST2 homodimer resembled that of the MST1 homodimer, the MST1–RASSF5 heterodimer showed distinct structural features. Firstly, the six N-terminal residues (Asp432–Lys437), which correspond to the short N-terminal 3{sub 10}-helix h1 kinked from the h2 helix in the MST1 homodimer, were disordered. Furthermore, the MST1 SARAH domain in the MST1–RASSF5 complex showed a longer helical structure (Ser438–Lys480) than that in the MST1 homodimer (Val441–Lys480). Moreover, extensive polar and nonpolar contacts in the MST1–RASSF5 SARAH domain were identified which strengthen the interactions in the heterodimer in comparison to the interactions in the homodimer. Denaturation experiments performed using urea also indicated that the MST–RASSF heterodimers are substantially more stable than the MST homodimers. These findings provide structural insights into the role of the MST1–RASSF5 SARAH domain in apoptosis signalling.« less
  • The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E-cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia-orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-γ (PPARγ), and the involvement of Hippo pathway members, as regulators of transcription factors. Tomore » give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1α and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARγ activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1α nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1α protein; under this experimental condition HIF-1α appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1α in nuclei of human-bone metastasis. Thus, we identified Wwox as a novel molecule in the HIF-1α-HDM2 regulatory loop, necessary for the dynamic regulation of the HIF-1α amount, and we suggested that the reduction of endogenous Wwox free pool under hypoxia might also be due to the interaction with HDM2, sequestering the E3 ubiquitin ligase. We highlighted the importance of nuclear HIF-1α in the biology of metastasis for the mesenchymal-epithelial transition: this phenotype was regulated by Wwox plus hypoxia through E-cadherin target gene, playing a pivotal role in bone metastasis colonization. - Highlights: • E-cadherin accumulates in hypoxic bone metastasis opposite to primary carcinoma. • HIF-1 and PPARγ cooperate in inducing E-cadherin under hypoxia in metastatic cells. • Wwox regulates HIF-1α phosphorylation and nuclear translocation. • Hypoxia plus Wwox prevent HIF-1α degradation via HDM2 forming a regulatory loop.« less
  • In Rhodbacter sphaeroides, transcriptional response to singlet oxygen is controlled by the ECF (extracytoplasmic function) transcription factor, σ Ε. ECF σ’s comprise the largest and most divergent group of the σ 70-family members and are negatively regulated by their cognate anti-σ factor. Here, we determine the crystal structure of the Rhodobacter sphaeroides ECF σ factor, σE, in an inhibitory complex with its anti-σ, ChrR. The structure reveals that ChrR is composed of two structural domains separated by a flexible linker. The N-terminal domain sterically occludes the two primary binding determinants on σE for core RNA polymerase and is thus referredmore » to as the ASD (anti-σ domain). Genetic and biochemical characterization of the two domains show that the ASD is sufficient to inhibit σE dependant transcription and the C-terminal domain is required for response to singlet oxygen and the release of σE from the ASD. In addition, structural and sequence analyses of the ASD of ChrR and other ECF anti-σ’s, reveal that the N-terminal domain of different groups of ECF anti-σ’s share a common structural fold with some sequence similarity. Bioinformatics studies show that the ASD occurs in as many as one third of ECF anti-σ’s, many of which have diverse C-terminal domains. The conserved ASD are sometimes fused to diverse C-terminal domains. These studies reveal that the ASD class of anti-σ’s are extraordinarily diverse, based on the type of σ Ε factors they are associated with and the C-terminal domains to which they are linked.« less