scholarly journals Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

2021 ◽  
pp. 1-11
Author(s):  
Julia Sleutjes ◽  
Lotte Kleimeier ◽  
Erika Leenders ◽  
Willemijn Klein ◽  
Jos Draaisma
Keyword(s):  
Systematic Review ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Nuchal Translucency ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Signalling Pathway ◽  
Lymphatic Abnormalities ◽  
Pathogenic Variants ◽  
Spectrum Disorders ◽  
Mapk Inhibitors

Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic <i>PTPN11</i> variant<i>s</i> to 38% in patients with pathogenic <i>RIT1</i> variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic <i>SOS1</i> to 29% in patients with pathogenic <i>RIT1</i> variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic <i>PTPN11</i> variants to 44% in patients with pathogenic <i>SOS1</i> variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic <i>RIT1</i> variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.

scholarly journals An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

2017 ◽  
Vol 214 (6) ◽  
pp. 1691-1710 ◽  
Author(s):  
Helen L. Young ◽  
Emily J. Rowling ◽  
Mattia Bugatti ◽  
Emanuele Giurisato ◽  
Nadia Luheshi ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Acquired Resistance ◽  
Drug Tolerance ◽  
Mapk Signaling ◽  
Signaling Network ◽  
Mitogen Activated Protein Kinase ◽  
Cytokine Signaling ◽  
Adaptive Responses ◽  
Mapk Inhibitors

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.

scholarly journals The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

2020 ◽  
Vol 21 (8) ◽  
pp. 2773 ◽  
Author(s):  
Angelina Pranteda ◽  
Valentina Piastra ◽  
Lorenzo Stramucci ◽  
Deborah Fratantonio ◽  
Gianluca Bossi
Keyword(s):  
Colorectal Carcinoma ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Chemotherapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
High Expectations ◽  
P38 Mapk Pathway ◽  
Mapk Inhibitors ◽  
Signaling Activation

Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes.

Extracellular cysteine/cystine redox regulates the p44/p42 MAPK pathway by metalloproteinase-dependent epidermal growth factor receptor signaling

2005 ◽  
Vol 289 (1) ◽  
pp. G70-G78 ◽  
Author(s):  
Yvonne S. Nkabyo ◽  
Young-Mi Go ◽  
Thomas R. Ziegler ◽  
Dean P. Jones
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Redox State ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Epidermal Growth ◽  
Mapk Inhibitors

Previous research shows that stimulation of proliferation of colon carcinoma (Caco-2) cells by a more reduced extracellular cysteine/cystine (Cys/CySS) redox state occurs with no apparent effect on intracellular glutathione and that this stimulation is lost on addition of epidermal growth factor. The purpose of the present study was to determine whether a more reduced extracellular Cys/CySS redox state activates the mitogenic p44/p42 mitogen-activated protein kinase (MAPK) pathway and whether this is signaled through the epidermal growth factor receptor (EGFR). Caco-2 cells were exposed to a range of physiological extracellular redox conditions from −150 to 0 mV. In the absence of added growth factors, the most reduced (−150 mV) redox state induced an 80% increase in EGFR phosphorylation, and this was followed by a marked increase in phosphorylation of p44/p42 MAPK. Inhibitors of EGFR (AG1478) and p44/p42 MAPK (U0126) phosphorylation blocked redox-dependent p44/p42 phosphorylation, indicating that signaling occurred by EGFR. These effects were inhibited by pretreatment with a nonpermeant alkylating agent, showing that signaling involved thiols accessible to the extracellular space. The EGFR ligand TGF-α was increased in culture medium at more reduced redox states. Redox-dependent phosphorylation of EGFR was completely prevented by a metalloproteinase inhibitor (GM6001), and an antibody to TGF-α partially inhibited the phosphorylation of p44/p42 MAPK by redox. Thus the data show that a redox-dependent activation of metalloproteinase can stimulate the mitogenic p44/p42 MAPK pathway by a TGF-α-dependent mechanism. Because Cys availability and Cys/CySS redox are dependent on nutrition, disease, and environmental exposures, the results suggest that cell proliferation could be influenced physiologically by Cys-dependent redox effects on growth factor signaling pathways.

scholarly journals Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling

2010 ◽  
Vol 30 (19) ◽  
pp. 4698-4711 ◽  
Author(s):  
Manuela Molzan ◽  
Benjamin Schumacher ◽  
Corinna Ottmann ◽  
Angela Baljuls ◽  
Lisa Polzien ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Noonan Syndrome ◽  
Developmental Disorders ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Membrane Recruitment ◽  
Protein Protein Interaction ◽  
Binding Data ◽  
Mitogen Activated Protein

ABSTRACT The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser259, a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By presenting biophysical binding data, the 14-3-3/C-RAFpS259 crystal structure, and cellular analyses, we indicate a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer259/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway.

scholarly journals Decreased Phosphorylated ERK 1/2 in Individuals with Autism

2019 ◽  
Author(s):  
Anthony Russo ◽  
Albert Mensah ◽  
Judith Bowman
Keyword(s):  
Intracellular Signaling ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Autism Spectrum ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Spectrum Disorders

Autism spectrum disorders (ASDs) are complex, highly heritable neurodevelopmental disorders affecting ∼1 in 60-100 children. The extracellular signal-regulated kinases, ERK1 and ERK2, are central elements of one of the most prominent intracellular signaling cascades, the mitogen activated protein kinase (MAPK) pathway. They are genetically linked to ASDs and other syndromes typified by intellectual disability. In this study, we measured the concentration of phosphorylated (activated) ERK 1 and 2. We present evidence that ERK is decreased in individuals with autism, and that ERK levels are associated with decreased Epidermal Growth Factor Receptor (EGFR).

scholarly journals Integrated Molecular Characterisation of the MAPK Pathways in Human Cancers

2020 ◽  
Author(s):  
Musalula Sinkala ◽  
Panji Nkhoma ◽  
Nicola Mulder ◽  
Darren Patrick Martin
Keyword(s):  
Cancer Cells ◽  
Large Scale ◽  
Mapk Pathway ◽  
Gene Knockout ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Signalling Pathway ◽  
Mapk Pathways ◽  
Human Cancers ◽  
Mitogen Activated Protein ◽  
Molecular Aberrations

AbstractThe mitogen-activated protein kinase (MAPK) pathways are a crucial regulator of the cellular processes that fuel the malignant transformation of normal cells. The genetic underpinnings of molecular aberrations which lead to cancer involve mutations in and, transcription variations of, various MAPK pathway genes. Here, we use datasets of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We identify the subset of these genes within which mutations tend to be associated with the worst disease outcomes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the responses of cancer cells to MAPK drug perturbations: a revelation with great potential for guiding the development of innovative therapeutic strategies.

scholarly journals A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1618 ◽  
Author(s):  
Braicu ◽  
Buse ◽  
Busuioc ◽  
Drula ◽  
Gulei ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Mapk Pathway ◽  
Alternative Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Management ◽  
Pathway Activation ◽  
Promising Therapeutic Target ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

scholarly journals The mitogen-activated protein kinase pathway tonically inhibits both basal and IGF-I-stimulated IGF-binding protein-5 production in mammary epithelial cells

2007 ◽  
Vol 194 (2) ◽  
pp. 349-359 ◽  
Author(s):  
Jodie M Fleming ◽  
Jeffrey A Brandimarto ◽  
Wendie S Cohick
Keyword(s):  
Mammary Epithelial Cells ◽  
Mapk Pathway ◽  
Mammary Epithelial ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Igf I ◽  
Mitogen Activated Protein ◽  
Igf Binding ◽  
Mapk Inhibitors ◽  
Igfbp 3

The IGF system plays a key role in mammary gland growth and development. Our lab previously reported that IGF-I primarily regulates IGF-binding protein (BP)-3 in bovine mammary epithelial cells (MEC) and IGFBP-5 in mammary fibroblasts (MF). Presently, we examined the signaling pathways used by IGF-I to elicit this distinct, cell-type specific regulation. The phosphatidylinositol-3 kinase pathway was required for IGF-I to increase IGFBP-3 and -5 in MF and IGFBP-3 in MEC. Surprisingly, inhibiting the mitogen-activated protein kinase (MAPK) pathway in MEC increased IGFBP-5 mRNA levels 2- to 4-fold under basal conditions and 8- to 12-fold in cells treated with IGF-I within 4 h. Similar patterns of IGFBP-3 and -5 regulation were observed in murine MEC. Cells treated with IGF-I in the presence of MAPK inhibitors secreted more IGFBP-5 protein into conditioned media relative to cells treated with IGF-I alone; however, IGFBP-5 protein was not detected in conditioned media of cells treated with only a MAPK inhibitor. The IGFBP-5 mRNA response to MAPK inhibitors was specific for MEC, as blocking MAPK activity decreased the ability of IGF-I to induce IGFBP-5 in MF. In addition, no other IGFBP was increased in either cell type when MAPK activity was inhibited. These increases in IGFBP-5 expression in response to inhibition of the MAPK pathway corresponded with the induction of apoptosis. In conclusion, we report the novel observation that the MAPK/extracellular signal regulated kinase (ERK) pathway specifically represses IGFBP-5 expression in MEC. The corresponding changes in apoptosis and IGFBP-5 expression support a role for this specific IGFBP in mammary gland involution.

RASopathies in multidisciplinary pediatric hospita

2020 ◽  
pp. 21-23
Author(s):  
Н.В. Журкова ◽  
Л.А. Гандаева ◽  
А.А. Пушков ◽  
Е.Н. Басаргина ◽  
А.В. Пахомов ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Inherited Diseases ◽  
Cardiofaciocutaneous Syndrome ◽  
Genes Encoding ◽  
Mitogen Activated Protein ◽  
Anagen Hair

RAS-патии - группа наследственных заболеваний, возникающая вследствие нарушения регуляции функции RAS/MAPK внутриклеточных путей (Ras/mitogen-activated protein kinase). Суммарная частота заболеваний данной группы - 1 случай на 1000 новорожденных. Наиболее часто среди RAS-патий встречается синдром Нунан. В настоящее время описано 13 генов, мутации которых отвечают за развитие данного заболевания, включая ген SHOC2, ассоциированный с Нунан-подобным синдромом и измененной структурой волос (Noonan-like syndrome with loose anagen hair) и ген LZTR1, мутации в котором приводят к развитию синдрома Нунан, тип 2 с аутосомно-рецессивным типом наследования. RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

The NRP1 gene regulates proliferation, apoptosis, migration, and invasion in T24 and 5637 bladder cancer cells

2020 ◽  
Author(s):  
Conghui Han ◽  
Yang Dong ◽  
Lin Hao ◽  
Kun Pang ◽  
Xiaoying Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Mapk Signalling Pathway ◽  
Neuropilin 1 ◽  
Mitogen Activated Protein

Abstract Background Bladder urothelial carcinoma (BC) is a fatal invasive malignancy and the most common malignancy of the urinary system. In the current study, we investigate the function and mechanisms of Neuropilin-1 (NRP1), the co-receptor for vascular endothelial growth factor, in BC pathogenesis and progression. Methods The expression of NRP1 was assessed in several BC cell lines. Additionally, the biological function of NRP1 in proliferation, apoptosis, angiogenesis, migration, and invasion of BC were validated in vitro by silencing NRP1. Moreover, gene expression profiling chip analysis was conducted, and the related signalling pathways were confirmed by Western blot to reveal the potential molecular mechanisms by which NRP1 promotes the malignant progression of BC. Results Overexpression of NRP1 was observed in several human BC cell lines. NRP1 knockdown inhibited cell proliferation, promoted apoptosis, and decreased angiogenesis, migration, and invasion in T24 and 5637 human BC cells. Microarray analysis results indicated that the expression of NRP1 was correlated with the levels of cyclin dependent kinase (CDK) 4, baculoviral IAP repeat containing 3, Cyclin E 2, CDK2, and AP-1 transcription factor subunit in BC. We also demonstrated that the biological function of NRP1was associated with activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Conclusions Our findings provide evidence that NRP1, as a potential tumour promoter, contributes to the metastasis and invasion of BC, which is associated with the activation of the MAPK pathway. Targeting NRP1 has the potential to become a new therapeutic strategy to benefit more patients with BC or other cancers.

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