Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192660 | GEO | 2022/12/27
REPOSITORIES: GEO
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Project description:Since loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-seq analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.
2023-03-10 | PXD030571 | Pride
Project description:Because loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-sequencing analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.ImplicationsWe provide evidence supporting a role for PAK inhibitors in treating NF2-deficient tumors. NF2-deficient tumors lacking Pak2 eventually adapt by kinome reprogramming, presenting opportunities for combination therapies to bypass anti-PAK drug resistance.
| S-EPMC9081258 | biostudies-literature
Project description:Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling
| PRJNA792572 | ENA
Project description:Cellular senescence is an irreversible cell growth arrest state linked to loss of tissue function and aging in mammals. The cellular transition from proliferation to senescence is marked by increased expression of the cell-cycle inhibitor p16INK4A and formation of senescence-associated heterochromatin foci (SAHF). It is known that SAHF formation depends primarily on HIRA-mediated nucleosome assembly of H3.3, and that the serine/threonine protein kinase Pak2 regulates HIRA-mediated nucleosome assembly of histone H3.3. Here, we tested the role of Pak2 in the regulation of cellular senescence. Depletion of Pak2 delays premature cellular senescence in both oncogene-induced senescence in human fibroblasts IMR90 cells and in oxidative stress induced senescence of mouse embryonic fibroblasts. Furthermore, overexpression of Pak2 promotes senescence of IMR90 cells. Importantly, depletion of Pak2 in mice delays the onset of some of the aging-associated phenotypes and extend life span of a progeroid mouse model. Lastly, we showed that Pak2 is required for expression of a group of genes involved in cellular senescence and regulates the deposition of newly synthesized H3.3 onto chromatin in senescent cells. Together, our results demonstrate that Pak2 is an important regulator of cellular senescence and organismal aging, in part through the regulation of gene expression and H3.3 nucleosome assembly.
2019-12-31 | GSE108081 | GEO
Project description:Macrophages play critical roles in immune function and are implicated as etiological agents in disease states such as cardiovascular disease and cancer. However, there is limited understanding of macrophage fitness molecular regulators, including survival, proliferation, and adhesion. This work identifies positive and negative regulators of macrophage fitness by harnessing the power of CRISPR/Cas9 whole genome screening technology. Here, we identified loss-of-function gene disruptions that caused mutant bone marrow-derived macrophages (BMDM) to decrease in culture abundance as supporters of macrophage fitness. Similarly, we identified genes that limit or suppress macrophage fitness by identifying those gene disruptions that caused BMDM to increase in abundance in cell culture. To do this, we analyzed the difference in frequency of sgRNA between the purified plasmid library used for lentiviral transfection versus the amplified sgRNA inserts from the DNA of BMDM following a 14-day post-viral transduction culture. With this approach, we identified gene disruptions to canonical essential genes, including previously described macrophage-specific essential genes such as Csf1r, as well as novel genes required for macrophage growth and survival. In addition, we also identified gene disruptions that increased macrophage abundance in culture, including canonical tumor suppressors such as p53 (Trp53) and cell cycle regulators (Cdkn1a/2a). Interestingly, targeting p21-activated kinase-2 (Pak2) led to those mutants becoming more productive, suggesting a novel role for Pak2 in suppressing macrophage fitness. Using targeted knockouts of PAK2, we show that PAK2 protein depletion affects NF2/Merlin-mediated downregulation of cyclin-d1. Further, this work indicates that PAK2 suppresses macropinocytic uptake in macrophages by modulating actin dynamics impacting pro-mitogenic signaling pathways downstream of macropinocytosis. Overall, this work shows how multiple pathways impact macrophage fitness and highlights the central role of PAK2 in macrophage fitness and macropinocytosis.
2024-05-01 | GSE251887 | GEO
Project description:Epigenetic mechanisms play an important role in the cellular development and maintenance of cellular homeostasis. Any alteration of epigenetic mechanisms via the changes in DNA methylation and histone modification may lead to various diseases including cancer. The differential expression of histone modifiers has been observed in various malignancies. We used microarray to detail the differential gene-expression pattern of head and neck (HNC) cancer cells upon depletion of p21 activated kinase (PAK2). we identified distinct class of downregulated genes, majorly associated with cellular proliferation and tumorigenesis.
2018-08-07 | GSE113322 | GEO
Project description:Merlin (Moesin-ezrin-radixin-like protein, also known as schwannomin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. Loss of function mutations or deletions in NF2 cause neurofibromatosis type 2 (NF2), a multiple tumor forming disease of the nervous system. NF2 is characterized by the development of bilateral vestibular schwannomas. Patients with NF2 can also develop schwannomas on other cranial and peripheral nerves, as well as meningiomas and ependymomas. The only potential treatment is surgery/radiosurgery, which often results in loss of function of the involved nerve. There is an urgent need for chemotherapies that slow or eliminate tumors and prevent their formation in NF2 patients. Interestingly NF2 mutations and merlin inactivation also occur in spontaneous schwannomas and meningiomas, as well as other types of cancer including mesothelioma, glioma multiforme, breast, colorectal, skin, clear cell renal cell carcinoma, hepatic and prostate cancer. Except for malignant mesotheliomas, the role of NF2 mutation or inactivation has not received much attention in cancer, and NF2 might be relevant for prognosis and future chemotherapeutic approaches. This review discusses the influence of merlin loss of function in NF2-related tumors and common human cancers. We also discuss the NF2 gene status and merlin signaling pathways affected in the different tumor types and the molecular mechanisms that lead to tumorigenesis, progression and pharmacological resistance.
| S-EPMC4615258 | biostudies-literature
Project description:Sonic Hedgehog subgroup medulloblastomas
| PRJNA384622 | ENA
Project description:Sivakumar2011 - Hedgehog Signaling Pathway
This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway.
References:
Hedgehog signaling in animal development: paradigms and principles.
Sonic hedgehog in the nervous system: functions, modifications and mechanisms.
Hedgehog signal transduction: recent findings.
Hedgehog signaling: Costal-2 bridges the transduction gap.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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2024-09-02 | BIOMD0000000395 | BioModels
Project description:Expression data after PAK2 knockdown in head and neck cancer cells
| PRJNA450818 | ENA