Control of the Hippo Pathway by Set7-Dependent Methylation of Yap

Oudhoff, Menno J.; Freeman, Spencer A.; Couzens, Amber L.; Antignano, Frann; Kuznetsova, Ekaterina; Min, Paul H; Northrop, Jeffrey P.; Lehnertz, Bernhard; Baršytė-Lovejoy, Dalia; Vedadi, Masoud; Arrowsmith, C.H.; Nishina, Hiroshi; Gold, Michael R.; Rossi, Fábio; Gingras, Anne‐Claude; Zaph, Colby

doi:10.1016/j.devcel.2013.05.025

Cited by 133 publications

(120 citation statements)

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“…We have recently identified a role for SETD7 in Hippo pathway signaling in vitro and in vivo (31). The Hippo pathway is an evolutionarily conserved regulator of cellular proliferation, survival, and organ size (32).…”

Section: Resultsmentioning

confidence: 99%

( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

Baršytė-Lovejoy

Oudhoff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Protein methyltransferases constitute an emerging but undercharacterized class of therapeutic targets with diverse roles in normal human biology and disease. Small-molecule “chemical probes” can be powerful tools for the functional characterization of such enzymes, and here we report the discovery of ( R )-PFI-2—a first-in-class, potent, highly selective, and cell-active inhibitor of the methyltransferase activity of SETD7 [SET domain containing (lysine methyltransferase) 7]—and two related compounds for control and chemoproteomics studies. We used these compounds to characterize the role of SETD7 in signaling, in the Hippo pathway, that controls cell growth and organ size. Our work establishes a chemical biology tool kit for the study of the diverse roles of SETD7 in cells and further validates protein methyltransferases as a druggable target class.

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Section: Resultsmentioning

confidence: 99%

( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

Baršytė-Lovejoy

Oudhoff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

159

165

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“…Functionally, the PDZ-binding domains are suggested to direct TAZ/YAP localization (Oka and Sudol, 2009;Remue et al, 2010). Mono-methylation of lysine 494 in YAP, which lies very close to the PDZ-binding domain, promotes the cytoplasmic retention of YAP (Oudhoff et al, 2013). Given this proximity it is reasonable to speculate that methylation might regulate the binding of YAP to PDZ-domain proteins, consequently impacting YAP localization.…”

Section: Structural Features Of Taz and Yapmentioning

confidence: 99%

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

2014

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Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.

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“…4,5 However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3, 13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear.…”

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confidence: 99%

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity. Cell Death and Differentiation (2014) 21, 1889-1899; doi:10.1038/cdd.2014.108; published online 15 August 2014Lysine methylation of non-histone proteins has recently emerged as a novel regulatory mechanism to control protein functions. 1-4Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) is a founding member of the family of non-chromatin lysine methyltransferases (KMTases). Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3,13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear. The beststudied targets of Set7/9-mediated methylation are p53 16 and E2 promoter-binding factor 1 (E2F1), 17 transcription factors involved in regulation of DNA damage response (DDR).In response to genotoxic stress cancer cells undergo cell-cycle arrest either in G1/S or G2/M or in both checkpoints. The presence of intact p53 in cancer cells mediates transient G1/S checkpoint arrest, 18,19 which allows cells to repair the damaged DNA before replication or, if the amount of damage is insurmountable, drives cells into apoptosis. 20,21On the contrary, the activity of the E2F family transcription factors, especially E2F1, drives cells from the G1/S block to mitosis. 22,23 Transcriptional activity of E2F1, in turn, is repressed by the retin...

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Control of the Hippo Pathway by Set7-Dependent Methylation of Yap

Cited by 133 publications

References 44 publications

( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

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