Yap1 Phosphorylation by c-Abl Is a Critical Step in Selective Activation of Proapoptotic Genes in Response to DNA Damage

Levy, Dan; Adamovich, Yaarit; Reuven, Nina; Shaul, Yosef

doi:10.1016/j.molcel.2007.12.022

Cited by 299 publications

(354 citation statements)

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“…In contrast, this treatment induced the level of the endogenous pro-apoptotic PIG3 and the pro-cell cycle arrest gene p21, the well-documented p53/p73 target genes. Under DNA damage c-Abl phosphorylates YAP, 24 and we therefore suspected that c-Abl plays a part in mediating this effect. Indeed, upon c-Abl depletion, CTGF expression under IR was partially restored (Figures 1b and c).…”

Section: Resultsmentioning

confidence: 98%

“…DNA damage activates YAP-p73 transcriptional activity through their phosphorylation by c-Abl. 13,24 In addition, the phosphorylation of YAP by c-Abl preferentially promotes its coactivation of pro-apoptotic genes by p73, as opposed to coactivation of Runx on non-apoptotic target genes, such as osteocalcin or Itch. 26 However, the question of how c-Abl-mediated YAP phosphorylation regulates TEAD coactivation remained open.…”

Section: Resultsmentioning

confidence: 99%

“…The phosphomimetic Y357E mutant is inefficient in TEAD coactivation. It is known that c-Abl phosphorylates YAP on tyrosine 357 that resides in the YAP transactivation domain 24 ( Figure 4a). To investigate whether YAP Y357 phosphorylation by c-Abl is sufficient to blunt YAP-TEAD activation, we used YAP Y357E, a phosphomimetic YAP mutant, and YAP Y357F, a non-phosphorylatable 'phosphodead' mutant.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we reported that under DNA damage c-Abl is activated and phosphorylates YAP at the Y357 residue (pY357). 24 YAP pY357 shows an increased association with p73 in targeting pro-apoptotic genes. Here we report that under DNA damage, the YAP-TEAD target genes are poorly expressed, that this inhibitory effect involves activation of c-Abl and that active c-Abl is sufficient in obtaining this effect.…”

Section: Discussionmentioning

confidence: 96%

“…23 We have previously found that like p73, 13 YAP is also a substrate of c-Abl and is phosphorylated at position Y357 in response to DNA damage. 24 YAP phosphorylated by c-Abl accumulates to higher levels, binds to p73 with higher affinity, and preferentially activates proapoptotic targets. Thus, in response to DNA damage, YAP functions as a tumor suppressor, in sharp contrast to the known oncogenic function of YAP under conditions described above.…”

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confidence: 99%

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c-Abl antagonizes the YAP oncogenic function

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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c-Abl antagonizes the YAP oncogenic function

et al. 2014

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YAPping about and not forgetting TAZ

et al. 2019

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The Hippo pathway has emerged as a major eukaryotic signalling pathway and is increasingly the subject of intense interest, as are the key effectors of canonical Hippo signalling, YES‐associated protein (YAP) and TAZ. The Hippo pathway has key roles in diverse biological processes, including network signalling regulation, development, organ growth, tissue repair and regeneration, cancer, stem cell regulation and mechanotransduction. YAP and TAZ are multidomain proteins and function as transcriptional coactivators of key genes to evoke their biological effects. YAP and TAZ interact with numerous partners and their activities are controlled by a complex set of processes. This review provides an overview of Hippo signalling and its role in growth. In particular, the functional domains of YAP and TAZ and the complex mechanisms that regulate their protein stability and activity are discussed. Notably, the similarities and key differences are highlighted between the two paralogues including which partner proteins interact with which functional domains to regulate their activity.

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Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling

Hergovich¹,

Hemmings²

2009

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The NDR/LATS family of kinases is a subgroup of the AGC group of protein kinases and is conserved from lower eukaryotes to humans. Like other AGC kinases, NDR/LATS kinases require phosphorylation of conserved Ser/Thr residues for activation. On the one hand, binding of the coactivator MOB to NDR/LATS allows autophosphorylation. On the other hand, MST kinases directly phosphorylate NDR/LATS kinases. In addition to our understanding of the molecular activation mechanisms, recent studies have shown that LATS kinases play a central role in Hippo/SWH (Salvador/Warts/Hippo) tumor suppressor pathways, which coordinate cell proliferation and apoptosis by regulating proto-oncogenes, such as YAP and TAZ. In this review, we summarize current knowledge of Merlin/MST/SAV/MOB/LATS/NDR/YAP/TAZ networks (also termed mammalian Hippo signaling) and their roles in mammalian cellular transformation.

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Yap1 Phosphorylation by c-Abl Is a Critical Step in Selective Activation of Proapoptotic Genes in Response to DNA Damage

Cited by 299 publications

References 50 publications

c-Abl antagonizes the YAP oncogenic function

c-Abl antagonizes the YAP oncogenic function

YAPping about and not forgetting TAZ

Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling

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