Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription

Li, Qi; Sun, Yangying; Jarugumilli, Gopala K.; Liu, Shun; Dang, Kyvan; Cotton, Jennifer L.; Xiol, Jordi; Chan, Pui Yee; DeRan, Michael; Ma, Lifang; Li, Rui; Zhu, Lihua Julie; Li, Joyce H.; Leiter, Andrew B.; Ip, Y. Tony; Camargo, Fernando D.; Luo, Xuelian; Johnson, Randy L.; Wu, Xu; Mao, Junhao

doi:10.1016/j.stem.2020.03.002

Cited by 130 publications

(126 citation statements)

References 92 publications

(120 reference statements)

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“…We computationally identified and genetically validated a role for Hippo signaling via Yap1 in the embryonic pulmonary mesenchyme. Mesenchymal Yap regulates smooth-muscle differentiation around the gastrointestinal epithelium 52 , and crosstalk between Wnt and Yap signaling regulates intestinal stem cell homeostasis 53 . Future investigations will elucidate how Yap influences airway smooth-muscle differentiation and whether cooperation with Wnt signaling is involved.…”

Section: Discussionmentioning

confidence: 99%

Patterning the embryonic pulmonary mesenchyme

Goodwin

Jaslove

Tao

et al. 2020

Preprint

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Smooth muscle guides morphogenesis of epithelia during development of several organs, including the mammalian lung. However, it remains unclear how airway smooth-muscle differentiation is spatiotemporally patterned and whether it originates from distinct mesenchymal progenitors. Using single-cell RNA-sequencing of embryonic mouse lungs, we show that the pulmonary mesenchyme contains a continuum of cell identities, but no distinct progenitors. Transcriptional variability correlates with sub-epithelial and sub-mesothelial mesenchymal compartments that are regulated by Wnt signaling. Live-imaging and tension sensors reveal patterned migratory behaviors and cortical forces in each compartment, and show that sub-epithelial mesenchyme gives rise to airway smooth muscle. Differentiation trajectory reconstruction reveals that cytoskeleton, adhesion, and Wnt signaling pathways are activated early in differentiation. Finally, we show that Wnt activation stimulates the earliest stages of differentiation and induces local accumulation of mesenchymal F-actin, which influences epithelial morphology. Our work provides the first single-cell view of pulmonary mesenchymal patterning during branching morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Patterning the embryonic pulmonary mesenchyme

Goodwin

Jaslove

Tao

et al. 2020

Preprint

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“…On the other hand, nuclear YAP1 inhibits transcription in β-catenin-active colon cancers via regulating chromatin state through the SWI/SNF complex [ 95 ]. Nuclear activation of endogenous YAP/TAZ stabilises TLE, an antagonist of the β-catenin-TCF4 transcriptional complex, which causes Wnt signalling suppression and loss of intestinal stem cells [ 96 ]. Cytoplasmic YAP plays suppressive functions in Wnt signalling outputs.…”

Section: Tcf/lef-independent β-Catenin Transcription Regulationmentioning

confidence: 99%

Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer

Dannappel

Wan

et al. 2020

Cells

163

111

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The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.

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“… 32 More recently, a vinylsulfonamide derivative ( 5 , DC-TEADin02 ) was developed via structure-based virtual screening and was shown to covalently bind to TEAD in cells transfected with Flag-TEAD4. 33 Triazole 6 efficiently inhibits TEAD palmitoylation in intestinal epithelium in vivo, 34 and compound 7 was identified via screening a DNA-ecoded library with indole-focused Ugi-peptidomimetics. 35 Furthermore, the hydroxyquinoline analogue 8 was reported to bind the central pocket, however, it activates the TEAD function.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket

et al. 2020

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Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, such as organogenesis and cell growth, and elevated TEAD activity is associated with tumorigenesis. Hence, novel modulators of TEAD and methods for their identification are in high demand. We describe the development of a new “thiol conjugation assay” for identification of novel small molecules that bind to the TEAD central pocket. The assay monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket by small molecules. Screening of a collection of compounds revealed kojic acid analogues as TEAD inhibitors, which covalently target the cysteine in the central pocket, block the interaction with coactivator yes-associated protein with nanomolar apparent IC 50 values, and reduce TEAD target gene expression. This methodology promises to enable new medicinal chemistry programs aimed at the modulation of TEAD activity.

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Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription

Cited by 130 publications

References 92 publications

Patterning the embryonic pulmonary mesenchyme

Patterning the embryonic pulmonary mesenchyme

Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer

Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket

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