scholarly journals RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions

2017 ◽  
Vol 215 (1) ◽  
pp. 319-336 ◽  
Author(s):  
Brandon Hogstad ◽  
Marie-Luise Berres ◽  
Rikhia Chakraborty ◽  
Jun Tang ◽  
Camille Bigenwald ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Phagocytic Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Myeloid Neoplasia

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

Thrombopoietin-Induced Activation of the Mitogen-Activated Protein Kinase (MAPK) Pathway in Normal Megakaryocytes: Role in Endomitosis

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
Ponlapat Rojnuckarin ◽  
Jonathan G. Drachman ◽  
Kenneth Kaushansky
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Geometric Mean ◽  
Critical Role ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signaling Domain

Thrombopoietin (TPO) plays a critical role in megakaryocyte proliferation and differentiation. Using various cultured cell lines, several recent studies have implicated the mitogen-activated protein kinase (MAPK) pathway in megakaryocyte differentiation. In the study reported here, we examined the role played by thrombopoietin-induced MAPK activity in a cytokine-dependent cell line (BAF3/Mpl) and in primary murine megakaryocytes. In both systems, extracellular signal-regulated protein kinase (ERK) 1 and 2 MAPK phosphorylation was rapidly induced by TPO stimulation. To identify the Mpl domain responsible for MAPK activation, BAF3 cells expressing truncated forms of the Mpl receptor were studied. Phosphorylation of ERKs did not require elements of the cytoplasmic signaling domain distal to Box 2 and was not dependent on phosphorylation of the adapter protein Shc. ERK activation in murine megakaryocytes was maximal at 10 minutes and was markedly decreased over the subsequent 3 hours. Next, the physiologic consequences of MAPK inhibition were studied. Using the MAPK kinase (MEK) inhibitor, PD 98059, blockade of MAPK activity substantially reduced TPO-dependent proliferation in BAF3/Mpl cells and markedly decreased mean megakaryocyte ploidy in cultures. To exclude an indirect effect of MAPK inhibition on stromal cells in whole bone marrow, CD41+ cells were selected and then cultured in TPO. The number of polyploid megakaryocytes derived from the CD41-selected cells was also significantly reduced by MEK inhibition, as was their geometric mean ploidy. These studies show an important role for MAPK in TPO-induced endomitosis and underscore the value of primary cells when studying the physiologic effects of signaling pathways.

Thrombopoietin-Induced Activation of the Mitogen-Activated Protein Kinase (MAPK) Pathway in Normal Megakaryocytes: Role in Endomitosis

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
Ponlapat Rojnuckarin ◽  
Jonathan G. Drachman ◽  
Kenneth Kaushansky
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Geometric Mean ◽  
Critical Role ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signaling Domain

Abstract Thrombopoietin (TPO) plays a critical role in megakaryocyte proliferation and differentiation. Using various cultured cell lines, several recent studies have implicated the mitogen-activated protein kinase (MAPK) pathway in megakaryocyte differentiation. In the study reported here, we examined the role played by thrombopoietin-induced MAPK activity in a cytokine-dependent cell line (BAF3/Mpl) and in primary murine megakaryocytes. In both systems, extracellular signal-regulated protein kinase (ERK) 1 and 2 MAPK phosphorylation was rapidly induced by TPO stimulation. To identify the Mpl domain responsible for MAPK activation, BAF3 cells expressing truncated forms of the Mpl receptor were studied. Phosphorylation of ERKs did not require elements of the cytoplasmic signaling domain distal to Box 2 and was not dependent on phosphorylation of the adapter protein Shc. ERK activation in murine megakaryocytes was maximal at 10 minutes and was markedly decreased over the subsequent 3 hours. Next, the physiologic consequences of MAPK inhibition were studied. Using the MAPK kinase (MEK) inhibitor, PD 98059, blockade of MAPK activity substantially reduced TPO-dependent proliferation in BAF3/Mpl cells and markedly decreased mean megakaryocyte ploidy in cultures. To exclude an indirect effect of MAPK inhibition on stromal cells in whole bone marrow, CD41+ cells were selected and then cultured in TPO. The number of polyploid megakaryocytes derived from the CD41-selected cells was also significantly reduced by MEK inhibition, as was their geometric mean ploidy. These studies show an important role for MAPK in TPO-induced endomitosis and underscore the value of primary cells when studying the physiologic effects of signaling pathways.

scholarly journals Three decades of progress from surgery to medical therapy for isolated neuroaxis BRAF V600E–positive Langerhans cell histiocytosis management: illustrative case

2021 ◽  
Vol 1 (19) ◽  
Author(s):  
Nallammai Muthiah ◽  
Kamil W. Nowicki ◽  
Jennifer L. Picarsic ◽  
Michael P. D’Angelo ◽  
Daniel F. Marker ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Clinical Manifestations ◽  
Tumor Burden ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Illustrative Case ◽  
Surgical Interventions ◽  
Mitogen Activated Protein

BACKGROUND “Langerhans cell histiocytosis” (LCH) is a term that encompasses single-system or multisystem disorders traditionally characterized by a proliferation of clonal CD1a+/CD207+ myeloid-derived histiocytes. In most cases of LCH, mitogen-activated protein kinase (MAPK) pathway somatic mutations lead to near universal upregulation of phosphorylated extracellular signal-regulated kinase expression. The clinical manifestations of LCH are numerous, but bone involvement is common. Intracranial lesions, especially as isolated manifestations, are rare. OBSERVATIONS The authors presented the case of a long-term survivor of exclusive intracranial LCH that manifested with isolated craniofacial bone and intraparenchymal central nervous system recurrences, which were managed with 3 decades of multimodal therapy. The patient was initially diagnosed with LCH at age 2 years, and the authors documented the manifestations of disease and treatment for 36 years. Most of the patient’s treatment course occurred before the discovery of BRAF V600E. Treatments initially consisted of chemotherapy, radiosurgery, and open resections for granulomatous LCH lesions. Into young adulthood, the patient had a minimal disease burden but still required additional radiosurgical procedures and open resections. LESSONS Surgical treatments alleviated the patient’s immediate symptoms and allowed for tumor burden control. However, surgical interventions did not cure the underlying, aggressive disease. In the current era, access to systemic MAPK inhibitor therapy for histiocytic lesions may offer improved outcomes.

Pulmonary Langerhans Cell Histiocytosis

2020 ◽  
Vol 41 (02) ◽  
pp. 269-279
Author(s):  
Brian Shaw ◽  
Michael Borchers ◽  
Dani Zander ◽  
Nishant Gupta
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Treatment Options ◽  
Skin Lesions ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Myeloid Neoplasm ◽  
Cystic Lung ◽  
Pulmonary Langerhans Cell Histiocytosis ◽  
Mitogen Activated Protein ◽  
The Central Nervous System

AbstractPulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is strongly associated with exposure to cigarette smoke. Recently, activating pathogenic mutations in the mitogen-activated protein kinase pathway have been described in the dendritic cells in patients with PLCH and have firmly established PLCH to be an inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly variable among individual patients, ranging from spontaneous resolution to development of pulmonary hypertension and progression to terminal respiratory failure. A subset of patients with PLCH may have extrapulmonary involvement, typically involving the skeletal system in the form of lytic lesions, skin lesions, or the central nervous system most commonly manifesting in the form of diabetes insipidus. Smoking cessation is the cornerstone of treatment in patients with PLCH and can lead to disease regression or stabilization in a substantial proportion of patients. Further insight into the underlying molecular pathogenesis of PLCH has paved the way for the future development of disease-specific biomarkers and targeted treatment options directed against the central disease-driving mutations.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

scholarly journals RecurrentNRASmutations in pulmonary Langerhans cell histiocytosis

2016 ◽  
Vol 47 (6) ◽  
pp. 1785-1796 ◽  
Author(s):  
Samia Mourah ◽  
Alexandre How-Kit ◽  
Véronique Meignin ◽  
Dominique Gossot ◽  
Gwenaël Lorillon ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lung Tissue ◽  
Langerhans Cell Histiocytosis ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Univariate Analysis ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Normal Lung ◽  
Pulmonary Langerhans Cell Histiocytosis

The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinasesBRAFandMAP2K1mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutatedBRAFandMAP2K1LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence ofBRAF,MAP2K1,NRASandKRASmutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAFV600Emutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harbouredNRASQ61K/Rmutations, whereas noNRASmutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11NRASQ61K/R-mutated pulmonary LCH lesions,BRAFV600Emutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrentBRAFandNRASmutations were carried by different cell clones.NRASQ61K/Rmutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrentBRAFV600EandNRASQ61K/Rmutations was significantly associated with patient outcome.These findings highlight the importance ofNRASgenotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

scholarly journals Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

2006 ◽  
Vol 26 (6) ◽  
pp. 2408-2418 ◽  
Author(s):  
Matthew Brook ◽  
Carmen R. Tchen ◽  
Tomas Santalucia ◽  
Joanne McIlrath ◽  
J. Simon C. Arthur ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Subcellular Localization ◽  
Protein Stability ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
P38 Mapk Pathway ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Sign in / Sign up

Export Citation Format

Share Document