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ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially  [cached]
Vantaggiato Chiara,Formentini Ivan,Bondanza Attilio,Bonini Chiara
Journal of Biology , 2006, DOI: 10.1186/jbiol38
Abstract: Background The mitogen-activated protein (MAP) kinases p44ERK1 and p42ERK2 are crucial components of the regulatory machinery underlying normal and malignant cell proliferation. A currently accepted model maintains that ERK1 and ERK2 are regulated similarly and contribute to intracellular signaling by phosphorylating a largely common subset of substrates, both in the cytosol and in the nucleus. Results Here, we show that ablation of ERK1 in mouse embryo fibroblasts and NIH 3T3 cells by gene targeting and RNA interference results in an enhancement of ERK2-dependent signaling and in a significant growth advantage. By contrast, knockdown of ERK2 almost completely abolishes normal and Ras-dependent cell proliferation. Ectopic expression of ERK1 but not of ERK2 in NIH 3T3 cells inhibits oncogenic Ras-mediated proliferation and colony formation. These phenotypes are independent of the kinase activity of ERK1, as expression of a catalytically inactive form of ERK1 is equally effective. Finally, ectopic expression of ERK1 but not ERK2 is sufficient to attenuate Ras-dependent tumor formation in nude mice. Conclusion These results reveal an unexpected interplay between ERK1 and ERK2 in transducing Ras-dependent cell signaling and proliferation. Whereas ERK2 seems to have a positive role in controlling normal and Ras-dependent cell proliferation, ERK1 probably affects the overall signaling output of the cell by antagonizing ERK2 activity.
Ras/Raf/MEK/ERK信号通路参与自噬调控作用的研究进展  [PDF]
王雪,张评浒
- , 2017,
Abstract: 自噬是机体保守的自我防御机制,是将细胞内变形坏死的细胞器和多余蛋白降解为小分子,以供循环利用。自噬在生理和病理状态下均发挥重要作用,可通过多条信号通路影响胞内物质的表达。目前已知Ras/Raf/MEK/ERK信号通路不仅广泛参与调控细胞生长、增殖、分化、凋亡等多个生理病理过程,并且参与调控自噬,并具有促进肿瘤细胞发生自噬性死亡的作用,但是其具体参与调控自噬的作用机制尚未完全阐明。本文就Ras/Raf/MEK/ERK信号通路参与调控自噬的作用的研究进展进行详细阐述,以期为研究Ras/Raf/MEK/ERK信号通路调控自噬的作用机制提供参考。
Autophagy is a conserved self-defense mechanism of organism, degrading the necrotic organelles and excess protein into small molecules for recycling. Autophagy plays a role in both physiological and pathological condition, influencing the expression of intracellular substance through multiple signaling pathways. Although it has been demonstrated that Ras/Raf/MEK/ERK signaling pathway was not only extensively involved in the regulation of cell growth, proliferation, differentiation and apoptosis, but was also implicated in autophagy and autophagic cell death, though its detailed mechanisms involved in regulation of autophagy has not been fully elucidated yet. This review focused on the advances of autophagy induced by Ras/Raf/MEK/ERK signaling pathway, to better understand the role of Ras/Raf/MEK/ERK signaling pathway in regulation of autophagy
Adaptor SKAP-55 Binds p21ras Activating Exchange Factor RasGRP1 and Negatively Regulates the p21ras-ERK Pathway in T-Cells  [PDF]
Helga Schneider, Hongyan Wang, Monika Raab, Elke Valk, Xin Smith, Matt Lovatt, Zhonglin Wu, Braudel Maqueira-Iglesias, Klaus Strebhardt, Christopher E. Rudd
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001718
Abstract: While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21ras and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21ras -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21ras activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21ras activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55?/? primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21ras becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21ras-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion.
Cardiac Hormones Target the Ras-MEK 1/2-ERK 1/2 Kinase Cancer Signaling Pathways  [PDF]
David L. Vesely
Cancers , 2011, DOI: 10.3390/cancers3011182
Abstract: The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor’s ability to stimulate ERK and Ras. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunocytochemical studies to inhibit DNA synthesis within cancer cells.
FGF signaling controls caudal hindbrain specification through Ras-ERK1/2 pathway
Ferran Aragon, Cristina Pujades
BMC Developmental Biology , 2009, DOI: 10.1186/1471-213x-9-61
Abstract: We show that in the chick hindbrain, Fgf3 is transcriptionally activated as early as 30 min after mvHnf1 electroporation, suggesting that it is a direct target of this transcription factor. We also analyzed the expression profiles of FGF activity readouts, such as MKP3 and Pea3, and showed that both are expressed within the hindbrain at early stages of embryonic development. In addition, MKP3 is induced upon overexpression of mFgf3 or mvHnf1 in the hindbrain, confirming vHnf1 is upstream FGF signaling. Finally, we addressed the question of which of the FGF-responding intracellular pathways were active and involved in the regulation of Krox20 and MafB in the hindbrain. While Ras-ERK1/2 activity is necessary for MKP3, Krox20 and MafB induction, PI3K-Akt is not involved in that process.Based on these observations we propose that vHnf1 acts directly through FGF3, and promotes caudal hindbrain identity by activating MafB and Krox20 via the Ras-ERK1/2 intracellular pathway.The hindbrain is the most posterior vesicle of the embryonic brain. During early steps of neural development, the hindbrain is transiently organized in segments along the anterior-posterior (AP) axis, which are called rhombomeres (r). This transient segmental organization is necessary for the correct specification of the different neuronal subtypes, the location of the cranial nerve exit points, and the migration streams of the neural crest cells from the dorsal hindbrain towards the branchial arches. Rhombomeres display a specific combinatory of gene expression that confers molecular identity to the rhombomeric territories, and they are compartment-like units with cell lineage restriction (for reviews see [2,3]).Refinement of the AP identities within the hindbrain requires the establishment of local signaling centers, which emit signals that pattern territories in their vicinity. Two signaling centers which emit FGF and WNT signals are located within the hindbrain: the Isthmic Organizer (IsO), at the l
PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors
Enrico K Schmidt, Serge Fichelson, Stephan M Feller
BMC Biology , 2004, DOI: 10.1186/1741-7007-2-7
Abstract: Biochemical studies with human cord blood-derived PEPs now show that Ras and the class Ib enzyme of the phosphatidylinositol-3 kinase (PI3K) family, PI3K gamma, are activated in response to minimal Epo concentrations. Surprisingly, three structurally different PI3K inhibitors block Ras, MEK and Erk activation in PEPs by Epo. Furthermore, Erk activation in PEPs is insensitive to the inhibition of Raf kinases but suppressed upon PKC inhibition. In contrast, Erk activation induced by stem cell factor, which activates c-Kit in the same cells, is sensitive to Raf inhibition and insensitive to PI3K and PKC inhibitors.These unexpected findings contrast with previous results in human primary cells using Epo at supraphysiological concentrations and open new doors to eventually understanding how low Epo concentrations mediate the moderate proliferation of erythroid progenitors under homeostatic blood oxygen levels. They indicate that the basal activation of MEKs and Erks in PEPs by minimal concentrations of Epo does not occur through the classical cascade Shc/Grb2/Sos/Ras/Raf/MEK/Erk. Instead, MEKs and Erks are signal mediators of PI3K, probably the recently described PI3K gamma, through a Raf-independent signaling pathway which requires PKC activity. It is likely that higher concentrations of Epo that are induced by hypoxia, for example, following blood loss, lead to additional mitogenic signals which greatly accelerate erythroid progenitor proliferation.Erythropoietin (Epo) is a multifunctional cytokine [1-4]. It has been known for a long time as a crucial regulator during all stages of definitive erythropoiesis. More recently, Epo was shown to have an important role in the survival of neurons after stress and injury [5-7]. Epo drives not only the proliferation of already committed early erythroid progenitor cells (burst-forming unit-erythroid; BFU-E), but also, and prominently, the proliferation and differentiation of later stage cells (colony-forming unit-erythroid; CFU-E
RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy  [PDF]
Ichiro Yajima,Mayuko Y. Kumasaka,Nguyen Dinh Thang,Yuji Goto,Kozue Takeda,Osamu Yamanoshita,Machiko Iida,Nobutaka Ohgami,Haruka Tamura,Yoshiyuki Kawamoto,Masashi Kato
Dermatology Research and Practice , 2012, DOI: 10.1155/2012/354191
Abstract: Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression. Cell signaling pathways are important for understanding not only cancer progression but also all life phenomena, including regulation of cell growth and death, migration, and angiogenesis [1–4]. Moreover, the events are accurately controlled by various intracellular signal transduction molecules [2, 5–7]. In cancer progression, the signaling is hyperactivated and/or silenced irreversibly. These irreversible losses of control in signal transduction allow cancers to acquire cancer-progression-specific phenotypes, such as antiapoptosis, abnormal proliferation, angiogenesis, and invasion. Previous studies revealed that collapse of signaling control was induced by both genetic and environmental factors [8–12]. Melanin-producing cells, acquired in several species from fungi to primates in the long evolutionary process, have many advantageous functions for survival strategy [13–19]. Melanocytes, melanin-producing cells that are the origin of melanoma, are developed from neural crest cells with several types of cell signaling pathways and gene expression [15, 20–22]. Human melanomas are categorized as nevus-associated melanomas and de novo melanomas based on their developmental process. Nevus-associated melanomas are transformants of preexisting benign lesions, and their malignant conversion progresses in a multistep manner [23–26]. De novo melanomas develop without pre-existing benign lesions [6, 27–29]. In humans, most melanomas are thought to have developed de novo. RFP-RET transgenic mice of line 304/B6 (RET mice) are powerful tools for analyses of melanoma with pre-existing benign lesions [6, 30, 31]. The entire process of melanoma development via
TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling
Paul M Campbell, Nadia Boufaied, James J Fiordalisi, Adrienne D Cox, Pierre Falardeau, Channing J Der, Henriette Gourdeau
Journal of Molecular Signaling , 2010, DOI: 10.1186/1750-2187-5-18
Abstract: To evaluate whether TLN-4601 interferes with K-Ras signaling, we utilized human pancreatic epithelial cells and demonstrate that TLN-4601 treatment resulted in a dose- and time-dependent inhibition of Ras-ERK MAPK signaling. The compound also reduced Ras-GTP levels and induced apoptosis. Finally, treatment of MIA PaCa-2 tumor-bearing mice with TLN-4601 resulted in antitumor activity and decreased tumor Raf-1 protein levels.These data, together with phase I/II clinical data showing tolerability of TLN-4601, support conducting a clinical trial in advanced pancreatic cancer patients.Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in North America and has a five-year survival rate of less than 5% [1]. Most patients with pancreatic cancer will die within six months of initial diagnosis. This poor prognosis has been related to the difficulty of detection in early stages of development, resulting in advanced disease at the time of presentation of first symptoms.To acquire malignancy, pancreatic ductal epithelial cells undergo a series of sequential genetic mutations. Among the initial events are KRAS mutations and HER-2/neu amplification, followed by the loss of p16INK4A/CDKN2 expression and then inactivation of p53 and DPC4/SMAD4 [2-4]. KRAS mutations occur in almost all cases of pancreatic cancer. The most common alterations are substitutions at the codon 12 glycine, producing constitutively active K-Ras [4-6]. K-Ras is a small GTPase that is a key player in various signaling pathways, working as a molecular switch to transmit signals from the cell membrane to the cytoplasm and nucleus [7,8]. A variety of extracellular signals (hormones and growth factors) activate Ras by causing the exchange of GDP with GTP. In one of the canonical signaling pathways, K-Ras recruits Raf kinases (Raf-1, B-Raf, or A-Raf) to the cell membrane where their own activation takes place. Once activated, Raf phosphorylates mitogen-activated protein kinases (MEK
Targeting Cadherin-17 Inactivates Ras/Raf/MEK/ERK Signaling and Inhibits Cell Proliferation in Gastric Cancer  [PDF]
Zhaohu Lin, Chao Zhang, Meifang Zhang, Danqing Xu, Yanfen Fang, Zheng Zhou, Xiaolong Chen, Ning Qin, Xiongwen Zhang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085296
Abstract: Cadherin-17 (CDH17), one member of 7D-cadherin superfamily, was overexpressed in gastric cancer (GC) and was associated with poor survival, tumor recurrence, metastasis, and advanced tumor stage. So far the cellular function and signaling mechanism of CDH17 in GC remains unclear. In this study, we showed that over 66% of GC cell lines (20/30) were CDH17 positive. Tissue microarray (TMA) assay showed that 73.6% Chinese GC tissues (159/216) were CDH17 positive, while 37% respective adjacent normal tissues were CDH17 positive. Knockdown of CDH17 inhibited cell proliferation, migration, adhesion and colony formation, and also induced a cell cycle arrest and apoptosis in AGS human GC cells. On the other side, overexpression of CDH17 facilitated MGC-803 GC tumor growth in nude mice. Antibody array and Western blotting assay demonstrated that knockdown of CDH17 in AGS cells down-regulated integrin β series proteins, further inactivated the Ras/Raf/MEK/ERK pathway and led to p53 and p21 accumulation, which resulted in proliferation inhibition, cell-cycle arrest and apoptosis induction. Collectively, our data firstly demonstrate the capacity of CDH17 to regulate the activity of Ras/Raf/MEK/ERK pathway for cell proliferation in GC, and suggest that CDH17 can serve as an attractive therapeutic target for future research.
Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway
Ya-Shih Tseng, Jenq-Chang Lee, Chi-Ying F Huang, Hsiao-Sheng Liu
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-435
Abstract: Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-ras mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either RasV12and wild-type Aurora-A (designated WT) or RasV12 and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved.Overexpression of wild-type Aurora-A and mutation of RasV12 were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the RasV12 transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the RasV12 transformants.Wild-type-Aurora-A enhances focus formation and aggregation of the RasV12 transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway.The role of Aurora-A, a serine/threonine kinase, in tumorigenesis has been reported [1-4]. In proliferative cells, the expression levels of Aurora-A mRNA and protein are low during G1 and S phases. The levels peak at G2 phase and fall during mitotic exit and G1 phase of the next cell cycle [3,5]. Aurora-A protein consists of 403 amino acids and has a molecular weight of 46 kilo Daltons (kDa) [5]. Overexpression of Aurora-A has been detected in several human cancer cell lines and cancers of the following tissues: bladder, breast, colon, liver, gingival, gliomas, medulloblastoma, ovarian, pancreas, prostate and tongue [6-16]. Ectopic expression of Aur
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