Activation of YAP-dependent Proliferation by a Small Molecule Targeting Annexin A2
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ABSTRACT:
PROVIDER: PRJNA691981 | ENA |
REPOSITORIES: ENA
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Project description:The transcriptional coactivator YAP orchestrates a pro-proliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse upon topical administration of drug. Chemical proteomics revealed the relevant target of PY-60 to be Annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase bound, non-phosphorylated, and transcriptionally active form of YAP. This work reveals ANXA2 to be a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale for promoting YAP-dependent regenerative repair in disease.
2021-01-14 | GSE164801 | GEO
Project description:Whole genome expression profiling in the presence and absence of annexin A2 [shRNA] identified fundamentally altered transcriptional programming that changes the radioresponsive transcriptome. Bioinformatics predicted that silencing AnxA2 may enhance cell death responses to stress in association with reduced activation of pro-survival signals such as nuclear factor kappa B. This prediction was validated by demonstrating a significant increase in sensitivity toward tumor necrosis factor alpha induced cell death in annexin A2 silenced cells, relative to vector controls, associated with reduced nuclear translocation of RelA (p65) following tumor necrosis factor alpha treatment. Murine progenitor cells, JB6 cell line, were stably transformed with Annexin A2 shRNA or vector only control and then treated with ionizing radiation at two doses, 10cGy and 100cGy. Samples were collected at 2hr, 6hr and 24hr for RNA isolation. Two untreated time points were collected also: 2hr and 24hr.
2012-11-28 | E-GEOD-42547 | biostudies-arrayexpress
Project description:Whole genome expression profiling in the presence and absence of annexin A2 [shRNA] identified fundamentally altered transcriptional programming that changes the radioresponsive transcriptome. Bioinformatics predicted that silencing AnxA2 may enhance cell death responses to stress in association with reduced activation of pro-survival signals such as nuclear factor kappa B. This prediction was validated by demonstrating a significant increase in sensitivity toward tumor necrosis factor alpha induced cell death in annexin A2 silenced cells, relative to vector controls, associated with reduced nuclear translocation of RelA (p65) following tumor necrosis factor alpha treatment.
2012-11-28 | GSE42547 | GEO
Project description:Repair of injured muscle involves repair of injured myofibers through the involvement of dysferlin and its interacting partners, including annexin. Studies with mice and patients have established that dysferlin deficit leads to chronic inflammation and adipogenic replacement of the diseased muscle. However, longitudinal analysis of annexin deficit on muscle pathology and function is lacking. Here we show that unlike annexin A1, but similar to dysferlin, lack of annexin A2 (AnxA2) causes poor myofiber repair and progressive weakening with age. However, unlike dysferlin-deficient muscle, AnxA2-deficient muscles do not exhibit chronic inflammation or adipogenic replacement. Deletion of AnxA2 in dysferlin deficient mice reduces inflammation, adipogenic replacement, and loss in muscle function caused by dysferlin deficit. These results show that: a) AnxA2 facilitates myofiber repair, b) chronic inflammation and adipogenic replacement of dysferlinopathic muscle requires AnxA2, and c) inhibiting AnxA2-mediated inflammation is a novel therapeutic avenue for dysferlinopathy.
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Project description:A mass-spec of proteins found bound to Annexin A2 following a immunoprecipitation of Annexin A2 from cell lysate of MDAMB231 cells plated 1) on plastic or 2) on collagen-1
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Project description:To investigate the role and mechanism of ANXA2 in retinal neovascularization, we used interfering and overexpressing lentivirus to intervene in HREC cells, respectively. Divided into interference group (negative control group and positive interference group), overexpression group (negative control group, overexpression positive control group). The mechanism of action of annexin A2 in human retinal vascular endothelium was explored by real-time PCR to quantify the expression of molecular genes in samples.
2022-08-20 | GSE136120 | GEO
Project description:In this work we use stable isotope labeling of amino acids in cell culture (SILAC) and a S. Typhimurium mutant that secretes increased amounts of effectors to identify cognate effector binding partners during infection. Using this method, we identified the host protein annexin A2 as a binding partner for both SopD2 and PipB2 and were able to confirm its binding to SopD2 by reciprocal pull down. This indicates that SopD2 and PipB2 likely both interact with annexin A2 through protein-protein interactions to establish the S. Typhimurium intracellular replicativeniche. This demonstrates the value of studying effector interactions using proteomic techniques and natural effector delivery during infection rather than transfection.
2022-02-17 | PXD025582 | Pride
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2024-02-22 | E-MTAB-13207 | biostudies-arrayexpress
Project description:The YAP pathway in regulating organ size by integrating external signals to control the expression of genes involved in cell proliferation. YAP is known to be involved in tumorigenesis in several tissues, yet its role in cholangiocarcinoma is not established We used microarrays to assess the role of YAP pathway in cholangiocarcinoma either by overexpressing a constitutively active YAP1 mutant, or by downregulating YAP1 expression using shRNA HuCCT1 cells where transfected with either a control scrambled shRNA or a shRNA targeting YAP1; cells were harvested, RNA was collected and analyzed using microarray
2015-10-27 | E-GEOD-61765 | biostudies-arrayexpress
Project description:We have previously established two sibling glioma subclones, J3T-1 and J3T-2, showing distinct invasive and angiogenic phenotypes. J3T-1, expressing high annexin A2, demonstrates robust angiogenesis and tumor invasion around neovasculature. J3T-2, expressing low annexin A2, demonstrates diffuse invasion along white matter tracts. Knockdown of annexin A2 in J3T-1 (J3T-1shA) resulted in diffuse invasion pattern, and overexpression of annexin A2 in J3T-2 (J3T-2A) showed prominent angiogenesis. We used microarrays to identify genes which promote the phenotypic transition regulated by annexin A2.
2020-04-20 | GSE138374 | GEO