YAP-dependent proliferation by a small molecule targeting annexin A2

Shalhout, Sophia Z; Yang, Pengyu; Grzelak, Edyta M.; Nutsch, Kayla; Shao, Sida; Zambaldo, Claudio; Iaconelli, Jonathan; Ibrahim, Lara; Stanton, Caroline; Chadwick, Stormi R; Chen, Emily; DeRan, Michael; Li, Sijia; Hull, Mitchell V.; Wu, Xu; Chatterjee, Arnab K.; Shen, Weijun; Camargo, Fernando D.; Schultz, Peter G.; Bollong, Michael J.

doi:10.1038/s41589-021-00755-0

Cited by 40 publications

(34 citation statements)

References 42 publications

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“…In addition to LPA, the conventional activator of YAP, a more specific and potent YAP activator, termed PY-60, has recently been developed. PY-60 is demonstrated to robustly activates YAP transcriptional activity in vitro and in vivo by targeting annexin A2 [19]. PY-60 holds therapeutic potential in pathological conditions aggravated by insufficient cell proliferation and repair.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated YAP is sequestered in the cytoplasm and degraded by ubiquitin-proteasome system (UPS). Conversely, when the Hippo pathway is inactivated, unphosphorylated YAP translocates into the nucleus where it associates with TEAD family transcription factors to regulate gene expression and promote cell proliferation [19,20]. The Hippo pathway has been demonstrated as the main locus where various pathways sensing cell density are integrated to mediate cell growth [21,22].…”

Section: Introductionmentioning

confidence: 99%

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YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

Liu

Zhu

et al. 2021

Cells

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Muscle stem cells (MuSCs) isolated ex vivo are essential original cells to produce cultured meat. Currently, one of the main obstacles for cultured meat production derives from the limited capacity of large-scale amplification of MuSCs, especially under high-density culture condition. Here, we show that at higher cell densities, proliferation and differentiation capacities of porcine MuSCs are impaired. We investigate the roles of Hippo-YAP signaling, which is important regulators in response to cell contact inhibition. Interestingly, abundant but not functional YAP proteins are accumulated in MuSCs seeded at high density. When treated with lysophosphatidic acid (LPA), the activator of YAP, porcine MuSCs exhibit increased proliferation and elevated differentiation potential compared with control cells. Moreover, constitutively active YAP with deactivated phosphorylation sites, but not intact YAP, promotes cell proliferation and stemness maintenance of MuSCs. Together, we reveal a potential molecular target that enables massive MuSCs expansion for large-scale cultured meat production under high-density condition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

Liu

Zhu

et al. 2021

Cells

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“…As Anxa2 expression and phosphor-Tyr23 are largely evaluated in various cancer types [16][17][18][19][20][21]34], this regulatory mechanism towards STAT3 somehow outstands as an assignable target for STAT3 inhibition. Anxa2 has been proven facilitating cancer progression via multiple aspects by interacting with other biomolecules, among which the Anxa2 rearrangement gene expression in cancer cells through oncogenic transcription factor like NF-κB, YAP1 in Hippo pathway and STAT3/6 [22,26]. In our previous research, (20S)G-Rh2 is indicated as a natural inhibitor for Anxa2 and depresses NF-κB activation via Anxa2-p50 subunit interaction [27,28].…”

Section: Discussionmentioning

confidence: 97%

“…Recent researches on cancers indicate that Anxa2 is over-expressed in various types of cancers, promotes cancer development, metastasis and chemo-resistance, highly associated with poor prognosis [16][17][18][19][20][21]. Detailed mechanisms are revealed that Anxa2 interacts with transcriptional factors and enhances their activation including NF-κB, STAT3/6 and YAP1 [22][23][24][25][26]. In our previous work, we have already identified Anxa2 as a cellular target of (20S) ginsenoside Rh2((20S)G-Rh2), a natural ginseng extract with anti-cancer activity, and (20S)G-Rh2 inhibited NF-κB activation by interfering Anxa2-NF-κB p50 subunit interaction [27,28].…”

Section: Introductionmentioning

confidence: 99%

(20S) Ginsenoside Rh2 Inhibits STAT3/VEGF Signaling by Targeting Annexin A2

Wang

Chen

Zhang

et al. 2021

IJMS

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Signal transducers and activators of transcription 3 (STAT3) acts as a transcriptional signal transducer, converting cytokine stimulation into specific gene expression. In tumor cells, aberrant activation of the tyrosine kinase pathway leads to excessive and continuous activation of STAT3, which provides further signals for tumor cell growth and surrounding angiogenesis. In this process, the tumor-associated protein Annexin A2 interacts with STAT3 and promotes Tyr705 phosphorylation and STAT3 transcriptional activation. In this study, we found that (20S) ginsenoside Rh2 (G-Rh2), a natural compound inhibitor of Annexin A2, inhibited STAT3 activity in HepG2 cells. (20S) G-Rh2 interfered with the interaction between Annexin A2 and STAT3, and inhibited Tyr705 phosphorylation and subsequent transcriptional activity. The inhibitory activity of STAT3 leaded to the negative regulation of the four VEGFs, which significantly reduced the enhanced growth and migration ability of HUVECs in co-culture system. In addition, (20S)G-Rh2 failed to inhibit STAT3 activity in cells overexpressing (20S)G-Rh2 binding-deficient Annexin A2-K301A mutant, further proving Annexin A2-mediated inhibition of STAT3 by (20S)G-Rh2. These results indicate that (20S)G-Rh2 is a potent inhibitor of STAT3, predicting the potential activity of (20S)G-Rh2 in targeted therapy applications.

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“…Given the tumour-suppressive nature of Hippo signalling components and the oncogenic nature of its effector transcription co-regulators, YAP and TAZ, targeting this pathway is a compelling therapeutic strategy to subvert cancer initiation and progression [52,53]. Further delineation of the underlying mechanism regulating Hippo signalling is expected to provide new and druggable targets for exploitation in cancer therapies.…”

Section: Dysregulation Of the Hippo Pathway In Cancersmentioning

confidence: 99%

Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

Lim

Lin

Seah

et al. 2021

Cells

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Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.

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YAP-dependent proliferation by a small molecule targeting annexin A2

Cited by 40 publications

References 42 publications

YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

(20S) Ginsenoside Rh2 Inhibits STAT3/VEGF Signaling by Targeting Annexin A2

Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

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