Search results for: PAK1
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#34084284 2021/05/25 To Up
Evaluation of liver kinase B1 downstream signaling expression in various breast cancers and relapse free survival after systemic chemotherapy treatment.LKB1-signaling has prominent roles in cancer development and metastasis. This report evaluates LKB1-signaling pathway gene expression associations with patient survival in overall breast cancer, specific subtypes, as well as pre- and post-chemotherapy. Subtypes analyzed were based on intrinsic molecular subtyping and traditional biomarker classifications. Intrinsic molecular subtypes included were Luminal-A, Luminal-B, HER2-enriched, and Basal-like. The biomarker subtypes assessed were Estrogen-Receptor Positive (ER+) and Negative (ER-), Wild-Type TP53 (WT-TP53) & Mutant-TP53, and Triple-Negative Breast Cancer (TNBC). Additionally, comparisons were made between these subtypes and breast cancer overall, and analyses between LKB1 signaling to patient survival before and after chemotherapy were made. We used the Kaplan-Meier Online Tool (KM Plotter) to correlate the relationship between mRNA expression of known LKB1 scaffolding proteins (CAB39 and LYK5), and downstream signaling targets (AMPK, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, PAK1, SIK1, SIK2, BRSK1, BRSK2, SNRK, and QSK), and patient survival across each subtype and treatment group. Our findings provide evidence that LKB1-signaling is associated with improved survival in overall breast cancer. Stratification into breast cancer subtypes show a more complicated relationship; NUAK2, for example, is correlated with improved survival in ER- but is worse in ER+ breast cancer. In evaluating the association of LKB1-signaling pathway expression with relapse free survival of varying breast cancer tumors exposed to chemotherapy or treatment-naive tumors, our data provides baseline knowledge for understanding the pathway dynamics that affect survival and therefore are linked to pathology. This establishes a foundation for studying LKB1 targets with the goal of identifying druggable targets.
Khoa Nguyen, Andrew Rivera, Madlin Alzoubi, Henri Wathieu, Shengli Dong, Hassan Yousefi, Margarite Matossian, Suresh Alahari, David Drewry, Matthew Burow, Bridgette Collins-Burow
1480 related Products with: Evaluation of liver kinase B1 downstream signaling expression in various breast cancers and relapse free survival after systemic chemotherapy treatment.7 inhibitors2 Pieces/Box8 inhibitors
#34075397 2021/06/01 To Up
PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2).Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well established function of Merlin is as a negative regulator of group A serine/threonine p21 activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.
Eric Hawley, Jeffrey Gehlhausen, Sofiia Karchugina, Hoi-Yee Chow, Daniela Araiza-Olivera, Maria Radu, Abbi Smith, Ciersten Burks, Li Jiang, Xiaohong Li, Waylan Bessler, Andrea Masters, Donna Edwards, Callie Burgin, David Jones, Charles Yates, D Wade Clapp, Jonathan Chernoff, Su-Jung Park
2021 related Products with: PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2).100.00 ug100ug Lyophilized100.00 ug100 ul100ug Lyophilized100 ul100ug Lyophilized5/100 Packing /sleeve/bo100ug Lyophilized0.1ml (1mg/ml)
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#34074054 2021/05/24 To Up
Ganoderic Acid A Promotes Amyloid-Î² Clearance (In Vitro) and Ameliorates Cognitive Deficiency in Alzheimer's Disease (Mouse Model) through Autophagy Induced by Activating Axl.Alzheimer's disease (AD) is thought to be caused by amyloid-Î² (AÎ²) accumulation in the central nervous system due to deficient clearance. The aim of the present study was to investigate the effect of ganoderic acid A (GAA) on AÎ² clearance in microglia and its anti-AD activity. AÎ² degradation in BV2 microglial cells was determined using an intracellular AÎ² clearance assay. GAA stimulated autophagosome formation via the Axl receptor tyrosine kinase (Axl)/RAC/CDC42-activated kinase 1 (Pak1) pathway was determined by Western blot analyses, and fluorescence-labeled AÎ²42 was localized in lysosomes in confocal laser microscopy images. The in vivo anti-AD activity of GAA was evaluated by object recognition and Morris water maze (MWM) tests in an AD mouse model following intracerebroventricular injection of aggregated AÎ²42. The autophagy level in the hippocampus was assayed by immunohistochemical assessment against microtubule-associated proteins 1A/1B light-chain 3B (LC3B). Intracellular AÎ²42 levels were significantly reduced by GAA treatment in microglial cells. Additionally, GAA activated autophagy according to increased LC3B-II levels, with this increased autophagy stimulated by upregulating Axl and Pak1 phosphorylation. The effect of eliminating AÎ² by GAA through autophagy was reversed by R428, an Axl inhibitor, or IPA-3, a Pak1 inhibitor. Consistent with the cell-based assay, GAA ameliorated cognitive deficiency and reduced AÎ²42 levels in an AD mouse model. Furthermore, LC3B expression in the hippocampus was up-regulated by GAA treatment, with these GAA-specific effects abolished by R428. GAA promoted AÎ² clearance by enhancing autophagy via the Axl/Pak1 signaling pathway in microglial cells and ameliorated cognitive deficiency in an AD mouse model.
Li-Feng-Rong Qi, Shuai Liu, Yu-Ci Liu, Ping Li, Xiaojun Xu
1348 related Products with: Ganoderic Acid A Promotes Amyloid-Î² Clearance (In Vitro) and Ameliorates Cognitive Deficiency in Alzheimer's Disease (Mouse Model) through Autophagy Induced by Activating Axl.96 tests96 tests96 tests96 tests100 ul50 ul4 Membranes/Box500 tests0.1ml100 μg
#34066419 2021/05/06 To Up
RAB7A Regulates Vimentin Phosphorylation through AKT and PAK.RAB7A is a small GTPase that controls the late endocytic pathway but also cell migration through RAC1 (Ras-related C3 botulinum toxin substrate 1) and vimentin. In fact, RAB7A regulates vimentin phosphorylation at different sites and vimentin assembly, and, in this study, we identified vimentin domains interacting with RAB7A. As several kinases could be responsible for vimentin phosphorylation, we investigated whether modulation of RAB7A expression affects the activity of these kinases. We discovered that RAB7A regulates AKT and PAK1, and we demonstrated that increased vimentin phosphorylation at Ser38 (Serine 38), observed upon RAB7A overexpression, is due to AKT activity. As AKT and PAK1 are key regulators of several cellular events, we investigated if RAB7A could have a role in these processes by modulating AKT and PAK1 activity. We found that RAB7A protein levels affected beta-catenin and caspase 9 expression. We also observed the downregulation of cofilin-1 and decreased matrix metalloproteinase 2 (MMP2) activity upon RAB7A silencing. Altogether these results demonstrate that RAB7A regulates AKT and PAK1 kinases, affecting their downstream effectors and the processes they regulate, suggesting that RAB7A could have a role in a number of cancer hallmarks.
Roberta Romano, Matteo Calcagnile, Azzurra Margiotta, Lorenzo Franci, Mario Chiariello, Pietro Alifano, Cecilia Bucci1 Set1 Set1 Set1 Set4 Sample Kit1 Set10x96, 2.0ml cultures50 ug1 Set1 Set1 Set1 Set
#34049799 2021/04/24 To Up
Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice.Several clinical studies have reported that hearing loss is correlated with autism in children. However, little is known about the underlying mechanism between hearing loss and autism. p21-activated kinases (PAKs) are a family of serine/threonine kinases that can be activated by multiple signaling molecules, particularly the Rho family of small GTPases. Previous studies have shown that Pak1 mutations are associated with autism. In the present study, we take advantage of Pak1 knockout (Pak1) mice to investigate the role of PAK1 in hearing function. We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell (HC) apoptosis and severe hearing loss. Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of Î²II-spectrin, which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1 mice. Overall, our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function. As the first candidate gene linking autism and hearing loss, Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.
Cheng Cheng, Yilin Hou, Zhonghong Zhang, Yanfei Wang, Ling Lu, Liyan Zhang, Pei Jiang, Song Gao, Qiaojun Fang, Chengwen Zhu, Junyan Gao, Xufeng Liu, Wei Xie, Zhengping Jia, Zhigang Xu, Xia Gao, Renjie Chai
2622 related Products with: Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice.1 kit100ug Lyophilized24 tests100ug Lyophilized1 kit100 ml.
#34031517 2021/05/24 To Up
Derivation of stationary distributions of biochemical reaction networks via structure transformation.Long-term behaviors of biochemical reaction networks (BRNs) are described by steady states in deterministic models and stationary distributions in stochastic models. Unlike deterministic steady states, stationary distributions capturing inherent fluctuations of reactions are extremely difficult to derive analytically due to the curse of dimensionality. Here, we develop a method to derive analytic stationary distributions from deterministic steady states by transforming BRNs to have a special dynamic property, called complex balancing. Specifically, we merge nodes and edges of BRNs to match in- and out-flows of each node. This allows us to derive the stationary distributions of a large class of BRNs, including autophosphorylation networks of EGFR, PAK1, and Aurora B kinase and a genetic toggle switch. This reveals the unique properties of their stochastic dynamics such as robustness, sensitivity, and multi-modality. Importantly, we provide a user-friendly computational package, CASTANET, that automatically derives symbolic expressions of the stationary distributions of BRNs to understand their long-term stochasticity.
Hyukpyo Hong, Jinsu Kim, M Ali Al-Radhawi, Eduardo D Sontag, Jae Kyoung Kim
1382 related Products with: Derivation of stationary distributions of biochemical reaction networks via structure transformation.5 G5 reactions100ug/vial96 tests4X1.25ml; 200 reactions (75 reactions100 reactions50мg/vial20000 UnitsUniversALL Extract Buffer20 ml30 Reactions
#34015583 2021/05/17 To Up
Emerging role of lncRNAs in the regulation of Rho GTPase pathway.The Ras homolog (Rho) family of small GTPases comprise several proteins with prominent roles in regulation of cell cycle transition, cell migration, and remodeling of actin cytoskeleton. Expression of these proteins is regulated by several factors among them are long non-coding RNAs (lncRNAs). The impact of lncRNAs on Rho GTPases signaling can be exerted through direct modulation of expression of these proteins or influencing expression of miRNAs that negatively regulate Rho GTPases. LINC00974/miR-122/RhoA, MALAT1/miR-429/RhoA, ZFAS1/miR-3924/RhoA/ROCK2, PCAT6/miR-326/RhoA/ROCK, SMILR/miR-141/RhoA/ROCK, DAPK1/miR-182/RhoA, GAS5/miR663a/RhoB, H19/miR-15b/CDC42/PAK1, TDRG1/miR-93/RhoC, TUG1/miR-498/CDC42, UCA1/miR-18a/Cdc42 and UCA1/miR-182/Cdc42 are examples of lncRNAs/miRNAs axes that regulate Rho GTPases. In the present manuscript, we describe the role of lncRNAs on Rho GTPases.
Soudeh Ghafouri-Fard, Rezvan Noroozi, Atefe Abak, Mohammad Taheri, Alireza Salimi2 Pieces/Box11 Set2 Pieces/BoxInhibitors2 Pieces/Box100 μg2 Pieces/Box2 Pieces/Box
#33994864 2021/04/24 To Up
ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway.Increasing evidence reveals that the Rho GTPase-activating protein is a crucial negative regulator of Rho family GTPase involved in tumorigenesis. The Rho GTPase-activating protein 25 (ARHGAP25) has been shown to specifically inactivate the Rho family GTPase Rac1, which plays an important role in pancreatic adenocarcinoma (PAAD) progression. Therefore, here we aimed to clarify the expression and functional role of ARHGAP25 in PAAD. The ARHGAP25 expression was lower in PAAD tissues than that in normal pancreatic tissues based on bioinformatics analysis and immunohistochemistry staining. Overexpression of ARHGAP25 inhibited cell growth of AsPC-1 human pancreatic cancer cells in vitro, while opposite results were observed in BxPC-3 human pancreatic cancer cells with ARHGAP25 knockdown. Consistently, in vivo tumorigenicity assays also confirmed that ARHGAP25 overexpression suppressed tumor growth. Mechanically, overexpression of ARHGAP25 inactivated AKT/mTOR signaling pathway by regulating Rac1/PAK1 signaling, which was in line with the results from the Gene set enrichment analysis on The Cancer Genome Atlas dataset. Furthermore, we found that ARHGAP25 reduced HIF-1Î±-mediated glycolysis in PAAD cells. Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD.
Wen-Kuan Huang, Yi Chen, Huafang Su, Tung-Ying Chen, Jiwei Gao, Yaxuan Liu, Chun-Nan Yeh, Shuijie Li
2762 related Products with: ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway.2 Pieces/Box2 Pieces/Box2ug100 μg100 ug/vial2ug96 wells (1 kit)8 Sample Kit
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