Autoinhibition of c-Abl

Pluk, Helma; Dorey, Karel; Superti‐Furga, Giulio

doi:10.1016/s0092-8674(02)00623-2

Cited by 226 publications

(181 citation statements)

References 42 publications

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“…Constitutively active c-Abl (Δ1-81 c-Abl) 28 Consistent with previous studies, 18 when overexpressed in MCF10A cells, YAP induced EMT, as evidenced by a fibroblast-like appearance and a dispersed cell distribution on a regular culture dish (Figure 2d, left panels). In contrast, MCF10A cells expressing YAP in the presence of active c-Abl displayed a cobblestone appearance similar to the control MCF10A cells.…”

Section: Resultssupporting

confidence: 90%

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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: Resultssupporting

confidence: 90%

“…18 c-Abl and Abl-PP), 28 and nuclear c-Abl, bearing no nuclear export signal (NES mutant c-Abl). 29 These results suggest that c-Abl inhibits YAP in coactivating TEAD, in EMTand enhanced migration induction, and in transforming MCF10A cells.…”

Section: Resultsmentioning

confidence: 99%

c-Abl antagonizes the YAP oncogenic function

et al. 2014

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“…The plasmids used were: pCDNA Flag-Yap1, 21 pSLX c-Abl WT and pSLX c-Abl D1-81, kindly provided by G Superti-Furga. 33 pCDNA c-Abl D1-81 was sub-cloned from pSLX c-Abl D1-81, and Flag-c-Abl D1-81 was constructed by inserting a Flag tag at the N-terminus of the construct. pSG5-c-Abl wt and kinase mutant are described in Agami et al 20 The 1b isoform was used for generation of full-length c-Abl constructs, and the numbering of c-Abl residues refers to positions in the 1b isoform.…”

Section: Methodsmentioning

confidence: 99%

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

et al. 2013

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The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.

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“…173 For example, the cellular form of the Abelson leukemia virus tyrosine kinase (c-Abl) is a large protein that consists of ~1150 residues whose N-terminal half includes an N-terminal "cap" of ~80 residues that is important for autoinhibition followed by an SH3 domain, an SH2 domain, and a tyrosine kinase domain. 174 The analysis of the c-Abl kinase crystal structure revealed that there is no clearly interpretable electron density for the ~80 residue N-terminal cap region. 175 Although SH3 domain possesses a characteristic fold consisting of five or six β-strands arranged in a form of two tightly packed anti-parallel β sheets, with the linker regions containing short helices, 173 it has been pointed out that extensive flexibility is necessary for target recognition.…”

Section: Intrinsic Disorder Protein Domains and Functionsmentioning

confidence: 99%

Functional Anthology of Intrinsic Disorder. 2. Cellular Components, Domains, Technical Terms, Developmental Processes, and Coding Sequence Diversities Correlated with Long Disordered Regions

et al. 2007

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Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes ~90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes and coding sequence diversities possessing strong positive and negative correlation with long disordered regions.

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Autoinhibition of c-Abl

Cited by 226 publications

References 42 publications

c-Abl antagonizes the YAP oncogenic function

c-Abl antagonizes the YAP oncogenic function

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

Functional Anthology of Intrinsic Disorder. 2. Cellular Components, Domains, Technical Terms, Developmental Processes, and Coding Sequence Diversities Correlated with Long Disordered Regions

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