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PREX1 as an activator of both PI3K/AKT and MAPK/ERK pathways. Receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs) activate PI3K that phosphorylates PIP 2 to PIP 3 . PIP 3 recruits PREX1 to the membrane via PH domain to convert Rac-GDP (inactive) to Rac-GTP (active). Activated Rac activates PI3K/p110β, triggering AKT signaling; active Rac also stimulates PAKmediated Raf/MEK/ERK signaling cascade.
Source publication
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway regulates cell growth, proliferation, survival, mobility and invasion. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is also an important mitogenic signaling pathway involved in various cellular progresses. AKT, also named protein kinase B (PKB), is a pri...
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Context 1
... as an activator of both AKT and ERK signaling: Phosphatidylinositol-3,4,5-trisphosphate (PIP 3 )-dependent Rac exchange factor 1 (PREX1) is a Rac guanine exchange factor (GEF) [76]. PREX1 activates both PI3K/AKT and MAPK/ERK signaling pathways promoting cancer cell proliferation (Fig. 3). Binding to PIP 3 through the PH domain, PREX1 is recruited onto plasma membrane where it activate Rho family GTPases Rac1/2/3 by exchanging associated GDP to GTP [77]. Active Rac can activate the p110β isoform of Class IA PI3K [78]; Rac also activates Raf/MEK/ERK signaling cascade through a PAK-mediated mechanism [79,80]. ...
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Citations
... Although multiple studies have suggested the roles of Akt and ERK in promoting drug resistance in a variety of cancer types [24][25][26] through distinct molecular mechanisms, the effects of these kinases on chemotherapy response in Ewing sarcoma have not been described. We treated MHH-ES-1 cells with either an Akt inhibitor (MK2206) or an ERK inhibitor (PD0325901). ...
Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.
... The Pi3K/akt/mammalian target of rapamycin (mTor) and MaPK/erK signaling pathways, which regulate fundamental cellular functions, are activated downstream from cell surface receptors, such as receptor tyrosine kinases and GPCRs (46). Mutations in the molecules involved in these pathways have been found in various types of cancer, and dysregulated signaling transduction plays an important role in mediating oncogenic signals, enhancing cancer cell growth, survival and metabolism (47). ...
... WT, wild-type; 2S, 2 sulfation. trials for anticancer agents targeting molecules in these pathways are being actively conducted (46,47,49). Several agents are used in clinical practice, such as alpelisib (Pi3K p110α inhibitor) and everolimus (mTor complex 1 inhibitor), which have been approved by the uS Food and drug administration for the treatment of advanced breast cancer (50). in the present study, thrombin-induced expression of p-akt and p-ERK was significantly inhibited by madanin-1 2S in both SKoV3 and Mda-MB-231 cells. ...
Thrombin, which plays a crucial role in hemostasis, is also implicated in cancer progression. In the present study, the effects of the thrombin-targeting recombinant tyrosine-sulfated madanin-1 on cancer cell behavior and signaling pathways compared with madanin-1 wild-type (WT) were investigated. Recombinant madanin-1 2 sulfation (madanin-1 2S) and madanin-1 WT proteins were generated using Escherichia coli. SKOV3 and MDA-MB-231 cells were treated with purified recombinant proteins with or without thrombin stimulation. Migration and invasion of cells were analyzed by wound healing assay and Transwell assay, respectively. Thrombin markedly increased cell migration and invasion in both SKOV3 and MDA-MB-231 cells, which were significantly suppressed by madanin-1 2S (P<0.05). Madanin-1 2S also significantly suppressed thrombin-induced expression of phosphorylated (p)-Akt and p-extracellular signal-regulated kinase in both cell lines (P<0.05), whereas madanin-1 WT had no effect on the expression levels of these proteins in MDA-MB-231 cells. Furthermore, madanin-1 2S significantly reversed the effects of thrombin on E-cadherin, N-cadherin and vimentin expression in MDA-MB-231 cells (P<0.05), whereas madanin-1 WT did not show any effect. In conclusion, madanin-1 2S suppressed the migration and invasion of cancer cells more effectively than madanin-1 WT. It is hypothesized that inhibiting thrombin via the sulfated form of madanin-1 may be a potential candidate for enhanced cancer therapy; however, further in vivo validation is required.
... Cym A does not only downregulate BCL-2 and MCL-1 but also upregulates BAX significantly, leading to the provoked MOMP-mediated cell death. Other cell survival-associated proteins, such as AKT and ERK, have shown their close link to tumorigenesis and lung cancer progression (Cao et al., 2019;Tan, 2020). Activated AKT via phosphorylation in cancer cells contributes to their survival, allowing them to withstand various cell death stimuli (Tan, 2020). ...
... Activated AKT via phosphorylation in cancer cells contributes to their survival, allowing them to withstand various cell death stimuli (Tan, 2020). While phosphorylated ERK mainly controls cell growth, proliferation, and differentiation, the overactivation of this protein has been found typically in up to 90% of lung cancers (Cao et al., 2019). The deactivation of AKT and ERK in lung cancer cells is also observed when treating cells with Cym A for 24 h. ...
Background: The upgrade of natural products for cancer treatment is essential since current anticancer drugs still pose severe side effects. Cymensifin A (Cym A) isolated from an orchid Cymbidium ensifolium has shown its potential to induce the death of several cancer cells; however, its underlying molecular mechanisms are hitherto unknown.
Methods: Here, we conducted a set of in vitro preliminary tests to assess the cytotoxic effects of Cym A on non-small-cell lung cancer (NSCLC) cells (A549, H23, H292, and H460). A flow cytometry system and Western blot analyses were employed to unveil molecular mechanisms underlying cancer cell apoptosis caused by Cym A.
Results: Cym A at 25-50 μM caused the death of all NSCLC cells tested, and its cytotoxicity was comparable to cisplatin, a currently used anticancer drug. The compound induced apoptosis of all NSCLC cells in a dose-dependent manner (5-50 μM), proven by flow cytometry, but H460 cells showed more resistance compared to other cells tested. Cym A-treated H460 cells demonstrated increased reactive oxygen species (ROS) and downregulated antioxidants (catalase, superoxide dismutase, and thioredoxin). The compound also upregulated the tumor suppressor P53 and the pro-apoptotic protein BAX but downregulated pro-survival proteins (BCL-2 and MCL-1) and deactivated survival signals (AKT and ERK) in H460 cells. Cym A was proven to trigger cellular ROS formation, but P53 and BAX were 2-fold more activated by Cym A compared to those treated with hydrogen peroxide. Our findings also supported that Cym A exerted its roles in the downregulation of nuclear factor erythroid 2-related factor 2 (a regulator of cellular antioxidant activity) and the increased levels of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase 3/7 during apoptosis.
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... Our results, graphically presented in the model shown in Fig. 5E, are consistent with the idea that increased tumor growth and augmented lung cancer and endothelial cell migration are linked to the positive effect of soluble BG, which increased HGF signaling leading to persistent phosphorylation of Met and activation of its downstream pathways, including PI3K/Akt/P-Rex1/Rac and Erk, relevant in cell migration and proliferation. Since PI3K/Akt and Erk pathways were simultaneously activated by HGF and their functional crosstalk at different levels has been reported to play a role in cancer progression, particularly in the process of metastatic dissemination [53,54], we cannot rule out that some crosstalk between these signaling pathways might be involved in the functional effects of enhanced HGF signaling by betaglycan. Our findings are consistent with previous studies showing that HGF is a potent inducer of lung cancer cell migration [36]. ...
... 34 Both AKT and ERK signalling are aberrantly activated in a wide range of human cancers. 35 Furthermore, our single-cell analysis revealed that parathyroid adenomas showed an immunosuppressive environment, particularly the increase in Treg count, despite the heterogeneity within the different adenoma samples. T reg cells are crucial for initiating tumour immune evasion. ...
Background
To date, because of the difficulty in obtaining normal parathyroid gland samples in human or in animal models, our understanding of this last-discovered organ remains limited.
Methods
In the present study, we performed a single-cell transcriptome analysis of six normal parathyroid and eight parathyroid adenoma samples using 10 × Genomics platform.
Findings
We have provided a detailed expression atlas of parathyroid endocrine cells. Interestingly, we found an exceptional high expression levels of CD4 and CD226 in parathyroid endocrine cells, which were even higher than those in lymphocytes. This unusual expression of lymphocyte markers in parathyroid endocrine cells was associated with the depletion of CD4 T cells in normal parathyroid glands. Moreover, CD4 and CD226 expression in endocrine cells was significantly decreased in parathyroid adenomas, which was associated with a significant increase in Treg counts. Finally, along the developmental trajectory, we discovered the loss of POMC, ART5, and CES1 expression as the earliest signature of parathyroid hyperplasia.
Interpretation
We propose that the loss of CD4 and CD226 expression in parathyroid endocrine cells, coupled with an elevated number of Treg cells, could be linked to the pathogenesis of parathyroid adenoma. Our data also offer valuable information for understanding the noncanonical function of CD4 molecule.
Funding
This work was supported by the 10.13039/501100012166National Key R&D Program of China (2022YFA0806100), 10.13039/501100001809National Natural Science Foundation of China (82130025, 82270922, 31970636, 32211530422), 10.13039/501100007129Shandong Provincial Natural Science Foundation of China (ZR2020ZD14), Innovation Team of Jinan (2021GXRC048) and the Outstanding University Driven by Talents Program and Academic Promotion Program of 10.13039/501100015507Shandong First Medical University (2019LJ007).
... vtRNA1-1 depletion resulted in an increased activation of the MAPK (mitogen-activated protein kinase) cascade, MAPK1/ERK2-MAPK3/ERK1, responsible for TFEB inactivation and cytoplasmic retention [55]. Kinases involved in signaling axes ERK1/2 MAPK and PI3K/Akt are described as autophagy regulators [92], cell growth, and proliferation modulators, and are involved in tumorigenesis (reviewed in [93]). ...
Non-coding RNAs have been described as crucial regulators of gene expression and guards for cellular homeostasis. Some recent papers are focused on vault RNAs, one of the classes of non-coding RNA, and their role in cell proliferation, tumorigenesis, apoptosis, cancer response to therapy, and autophagy, which made them potential therapy targets in oncology. In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complex. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that reminds a vault. Their sequence and structure are highly evolutionary conserved and show many similarities in comparison with different species, but vault RNAs show various roles. Vaults were discovered in 1986, and their functions remained unclear for many years. Although not much is known about their contribution to cell metabolism, it has become clear that vault RNAs are involved in various processes and pathways associated with cancer progression and modulating cell functioning in normal and pathological stages. In this review, we discuss known functions of the human vault RNAs in the context of cellular metabolism, emphasizing processes related to cancer and cancer therapy efficacy.
... Such interactions have been observed in other tumor types including melanoma, colorectal, pancreatic and breast carcinoma [30,31], and were also reported for CCA [15]. For review on the crosstalk of the pathways see: [32,33]. ...
Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.
... Identifying signaling pathways in antidepressant-resistant strains may lead to the development of new strategies for the treatment of depression. The MAPK/ERK and PI3K/AKT pathways are both important cellular signaling cascades which have been related to the regulation of cell growth, proliferation and survival/apoptosis [27]. In the present study we analyzed for the first time the ERK1/2 expression and phosphorylation in the hippocampus and mPFC of female WKY rats subjected to CMS. ...
... ERK1/2 and AKT have broad crosstalk between the two pathways (40). AKT can directly inhibit the ERK1/2 pathway via phosphorylation of Ser259 on RAF-1 or Ser364 and Ser428 on B-Raf, thus inhibiting Raf activity (41,42). ...
The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary mutations in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these mutations affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. We found that, in cells expressing the Shoc2 NSLH mutants, the AKT signaling pathway triggers the PAK activation, followed by phosphorylation and Raf-1/MEK1/2 /ERK1/2 signaling axis activation. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide evidence for the Shoc2 role as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.
... Also, the Kyoto Encyclopedia of Genes and Genomes database (KEGG) analysis reveals that G-rich peptide could downregulate the expression of many genes in the NF-kB signaling pathways (Fig. 3E, F). Previously studies indicated that PM 2.5-induced ROS production can trigger a number of redox-sensitive signaling pathways which result in diverse biological processes (such as inflammatory, the regulation of cell survival, and proliferation) through the oxidative stress-regulated MAPK/NF-kB pathway [54,55,56]. Consequently, NF-kB signaling pathways may be the most sensitive biological response to PM exposure and G-rich peptide treatment. ...
Rhizopus oligosporus was utilized in the solid-state fermentation of Chenopodiumformosanumsprouts (FCS) in a bioreactor. Subsequently, the antioxidant activity of food proteins derived from FCS was investigated. Results showed that glycine-rich peptide (GGGGGKP, G-rich peptide), identified from the <2 kDa FCS proteins, had antioxidant values. According to SwissADME, AllerTOP, ToxinPred, and BIOPEP-UWM analyses, G-rich peptide was identified as safe, non-toxic, and non-allergenic. Afterward, the peptide was examined using in silico and in vitro studies to evaluate its potential alleviating oxidative stress caused by particulate matter. This study proposed plausible mechanisms that involve the binding of G-rich peptide which inhibited phosphorylation of the v-rel avian reticuloendotheliosis viral oncogene homologA(RELA) subunit onNF-κB pathway. The inhibition then resulted in down regulation of NF-κB transcription and genetic expression of inflammatory responses. These findings suggested that G-rich peptide from FCS proteins can potentially alleviate oxidative stress.
