Drosophila Pez Acts in Hippo Signaling to Restrict Intestinal Stem Cell Proliferation

Poernbacher, Ingrid; Baumgartner, Roland; Marada, Suresh; Edwards, Kevin A.; Stocker, Hugo

doi:10.1016/j.cub.2012.01.019

Cited by 92 publications

(103 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[37][38][39][40][41][42] It was found that cytoplasmic PTPN14 inhibits oncogenic activity of YAP by binding and sequestering it from the nucleus. Interestingly, PTPN14 translocation to the nucleus is associated with induction of proliferation.…”

Section: Discussionmentioning

confidence: 99%

c-Abl antagonizes the YAP oncogenic function

et al. 2014

View full text Add to dashboard Cite

YES-associated protein (YAP) is a central transcription coactivator that functions as an oncogene in a number of experimental systems. However, under DNA damage, YAP activates pro-apoptotic genes in conjunction with p73. This program switching is mediated by c-Abl (Abelson murine leukemia viral oncogene) via phosphorylation of YAP at the Y357 residue (pY357). YAP as an oncogene coactivates the TEAD (transcriptional enhancer activator domain) family transcription factors. Here we asked whether c-Abl regulates the YAP-TEAD functional module. We found that DNA damage, through c-Abl activation, specifically depressed YAP-TEAD-induced transcription. Remarkably, c-Abl counteracts YAP-induced transformation by interfering with the YAP-TEAD transcriptional program. c-Abl induced TEAD1 phosphorylation, but the YAP-TEAD complex remained unaffected. In contrast, TEAD coactivation was compromised by phosphomimetic YAP Y357E mutation but not Y357F, as demonstrated at the level of reporter genes and endogenous TEAD target genes. Furthermore, YAP Y357E also severely compromised the role of YAP in cell transformation, migration, anchorage-independent growth, and epithelial-to-mesenchymal transition (EMT) in human mammary MCF10A cells. These results suggest that YAP pY357 lost TEAD transcription activation function. Our results demonstrate that YAP pY357 inactivates YAP oncogenic function and establish a role for YAP Y357 phosphorylation in cell-fate decision.

show abstract

Section: Discussionmentioning

confidence: 99%

c-Abl antagonizes the YAP oncogenic function

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Drosophila Pez is a newly identified component of the Hippo signalling pathway and specifically functions to restrict the growth of adult midgut epithelium 16 . To date, the degradation mechanism of Pez remains poorly defined.…”

Section: Su(dx) Governs Pez Stability Against Proteasomal Degradationmentioning

confidence: 99%

“…We used a functional GFP-tagged Pez (Pez-GFP), which is encoded by a genomic rescue construct, to indicate the endogenous Pez protein levels (Fig. 1d) 16 . Pez RNAi transgene (v40743) was expressed under the control of the patched-Gal4 (Ptc-Gal4) driver, which drives gene expression in a stripe of anterior compartment cells along the anterior/posterior (A/P) compartment boundary of imaginal discs.…”

Section: Su(dx) Governs Pez Stability Against Proteasomal Degradationmentioning

confidence: 99%

“…The Hippo signalling pathway has been shown to play an essential role in the regulation of ISC proliferation 15 . Pez has been identified as a negative upstream regulator of Yorkie (Yki), the Drosophila homologue of YAP, and is required for the activity of the Hippo pathway in the regulation of ISC proliferation 16 . However, how the stability and function of Pez are regulated remains unclear.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis

et al. 2015

View full text Add to dashboard Cite

Pez functions as an upstream negative regulator of Yorkie (Yki) to regulate intestinal stem cell (ISC) proliferation and is essential for the activity of the Hippo pathway specifically in the Drosophila midgut epithelium. Here we report that Suppressor of Deltex (Su(dx)) acts as a negative regulator of Pez. We show that Su(dx) targets Pez for degradation both in vitro and in vivo. Overexpression of Su(dx) induces proliferation in the fly midgut epithelium, which can be rescued by overexpressed Pez. We also demonstrate that the interaction between Su(dx) and Pez, bridged by WW domains and PY/PPxY motifs, is required for Su(dx)-mediated Pez degradation. Furthermore, we find that Kibra, a binding partner of Pez, stabilizes Pez via WW-PY/PPxY interaction. Moreover, PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. These results reveal a previously unrecognized mechanism of Pez degradation in maintaining the homeostasis of Drosophila midgut.

show abstract

“…Double mutations of these genes produce phenotypes closely resembling those caused by mutations of Hippo pathway components. In addition, Pez may activate the Hippo pathway by binding to Kibra (Poernbacher et al, 2012). The Fat protocadherin, a cell surface molecule, was also identified as an upstream regulator of the Hippo pathway (Bennett and Harvey, 2006;Cho et al, 2006;Silva et al, 2006;Willecke et al, 2006;Tyler and Baker, 2007).…”

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

View full text Add to dashboard Cite

This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

show abstract

Drosophila Pez Acts in Hippo Signaling to Restrict Intestinal Stem Cell Proliferation

Cited by 92 publications

References 58 publications

c-Abl antagonizes the YAP oncogenic function

c-Abl antagonizes the YAP oncogenic function

Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Contact Info

Product

Resources

About