c-Abl antagonizes the YAP oncogenic function

Keshet, Rom; Adler, Julia; Ricardo-Lax, Inna; Shanzer, Matan; Porat, Ziv; Reuven, Nina; Shaul, Yosef

doi:10.1038/cdd.2014.182

Cited by 50 publications

(45 citation statements)

References 49 publications

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“…We previously demonstrated that tyrosine phosphorylation of Yap affects its stability and activity. In that case, Yap is phosphorylated by c-Abl in response to DNA damage (21,27). Abl leads to stabilization of the Yap protein, a Taz paralog, which is dependent on Yap phosphorylation by Abl at Y357, corresponding to Taz phosphorylation by Src at Y316.…”

Section: Discussionmentioning

confidence: 99%

The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation

Shanzer

Adler

Ricardo-Lax

et al. 2017

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

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The polyomavirus middle T antigen (PyMT) oncogene activates the cellular nonreceptor tyrosine kinase c-Src and recruits the Hippo pathway effectors, Yap (yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif), as key steps in oncogenesis. Yap and Taz are transcription coactivators shuttling from the cytoplasm to the nucleus. The Hippo pathway kinase Lats1/2 (large tumor suppressor homolog) reduces Yap/Taz nuclear localization and minimizes their cytoplasmic levels by facilitating their ubiquitination by the E3 ligase SCF(β-TrCP). In contrast, PyMT increases the cytoplasmic Taz level. Here we show that this unique PyMT behavior is mediated by Src. We demonstrate that PyMT-induced Src activation inhibits degradation of both wild-type and tyrosine-less Taz, ruling out Taz modification as a mechanism of escaping degradation. Instead, we found that Src attenuates the SCF(β-TrCP) E3-ligase activity in blunting Taz proteasomal degradation. The role of Src in rescuing Taz from TrCP-mediated degradation gives rise to higher cell proliferation under dense cell culture. Finally, IkB (NF-kappa-B inhibitor), a known substrate of β-TrCP, was rescued by Src, suggesting a wider effect of Src on β-TrCP substrates. These findings introduce the Src tyrosine kinase as a regulator of SCF(β-TrCP).virus host interaction | middle T antigen | viral oncogene | Hippo pathway | SCF(β-TrCP)

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Section: Discussionmentioning

confidence: 99%

The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation

Shanzer

Adler

Ricardo-Lax

et al. 2017

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

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“…Next, we evaluated the effects of YAP1 phosphorylation sites on CH6953755 activity. Prior work has demonstrated that YES1 phosphorylation of YAP1 at the tyrosine 357 site regulated YAP1 transcriptional activity (13), so we examined the TEAD luciferase reporter activity when the following YAP1 mutations were being expressed: Y357E, which is phosphomimetic, or Y357F, which is phosphodead (19). Neither the YAP1 Y357E nor the Y357F mutation affected the suppression of YAP1 transcriptional activity by CH6953755 (Fig.…”

Section: Yap1 Plays a Role Downstream Of Yes1 In Yes1-amplified Cancermentioning

confidence: 99%

“…Serine-phosphorylated YAP1 localizes to cytoplasm and is degraded by proteasomes (16,18). Tyrosinephosphorylated YAP1 by YES1, SRC, LCK, or Abelson murine leukemia viral oncogene homolog (c-ABL) kinases is also reported, but its function seems context-dependent and has not been fully investigated (13,14,(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification

Hamanaka¹,

Nakanishi²,

Mizuno³

et al. 2019

Cancer Research

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Targeting genetic alterations of oncogenes by moleculartargeted agents (MTA) is an effective approach for treating cancer. However, there are still no clinical MTA options for many cancers, including esophageal cancer. We used a short hairpin RNA library to screen for a new oncogene in the esophageal cancer cell line KYSE70 and identified YES proto-oncogene 1 (YES1) as having a significant impact on tumor growth. An analysis of clinical samples showed that YES1 gene amplification existed not only in esophageal cancer but also in lung, head and neck, bladder, and other cancers, indicating that YES1 would be an attractive target for a cancer drug. Because there is no effective YES1 inhibitor so far, we generated a YES1 kinase inhibitor, CH6953755. YES1 kinase inhibition by CH6953755 led to antitumor activity against YES1-amplified cancers in vitro and in vivo. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1amplified cancers. YES1 regulated YAP1 transcription activity by controlling its nuclear translocation and serine phosphorylation. These findings indicate that the regulation of YAP1 by YES1 plays an important role in YES1-amplified cancers and that CH6953755 has therapeutic potential in such cancers. Significance: These findings identify the SRC family kinase YES1 as a targetable oncogene in esophageal cancer and describe a new inhibitor for YES1 that has potential for clinical utility. See related commentary by Rai, p. 5702

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“…Interestingly, YAP methylation by SET7 also results in cytoplasmic retention and decreased YAP transcriptional activity, a mechanism that seems to be of relevance in the maintenance of tissue homeostasis in the intestine (103). Another level of YAP regulation is mediated by tyrosine phosphorylation by YES, SRC, or c-ABL kinases (90, 104–106). However, the biological effects of tyrosine phosphorylation seem to be context dependent and can divert YAP transcriptional activity towards expression of pro- or anti-apoptotic genes, respectively (90, 104).…”

Section: Fine-tuning Yap/taz Activitymentioning

confidence: 99%

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Ehmer

Sage

2016

Molecular Cancer Research

122

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The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. While the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor suppressive attributes of YAP/TAZ are reviewed which emphasizes the relevance of the Hippo pathway in cancer.

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c-Abl antagonizes the YAP oncogenic function

Cited by 50 publications

References 49 publications

The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation

The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation

YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

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