The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors

Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most odontogenic tumors remains unclear, there have been some advances, recently, in the understanding of the genetic basis of specific odontogenic tumors. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway is intimately involved in the regulation of important cellular functions, and it is commonly deregulated in several human neoplasms. Molecular analysis performed by different techniques, including direct sequencing, next-generation sequencing, and allele-specific qPCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway in odontogenic tumors. Genetic mutations in this pathway genes have been reported in epithelial and mixed odontogenic tumors, in addition to odontogenic carcinomas and sarcomas. Notably, B-Raf proto-oncogene serine/threonine kinase (BRAF) and KRAS proto-oncogene GTPase (KRAS) pathogenic mutations have been reported in a high proportion of ameloblastomas and adenomatoid odontogenic tumors, respectively. In line with the reports about other neoplasms that harbor a malignant counterpart, the frequency of BRAF p.V600E mutation is higher in ameloblastoma (64% in conventional, 81% in unicystic, and 63% in peripheral) than in ameloblastic carcinoma (35%). The objective of this study was to review MAPK/ERK genetic mutations in benign and malignant odontogenic tumors. Additionally, such genetic alterations were discussed in the context of tumorigenesis, clinical behavior, classification, and future perspectives regarding therapeutic approaches.

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IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.25.18.7940-7952.2005 ◽

2005 ◽

Vol 25 (18) ◽

pp. 7940-7952 ◽

Cited By ~ 140

Author(s):

Monideepa Roy ◽

Zhigang Li ◽

David B. Sacks

Keyword(s):

Growth Factor ◽

Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

Cellular Functions ◽

Molecular Scaffold ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Erk Activity

ABSTRACT IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.

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

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1081-1095.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1081-1095 ◽

Cited By ~ 101

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.

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Defects of the Carney complex gene (PRKAR1A) in odontogenic tumors

Endocrine Related Cancer ◽

10.1530/erc-15-0094 ◽

2015 ◽

Vol 22 (3) ◽

pp. 399-408 ◽

Cited By ~ 4

Author(s):

Sílvia F Sousa ◽

Ricardo S Gomez ◽

Marina G Diniz ◽

Vanessa F Bernardes ◽

Flávia F C Soares ◽

...

Keyword(s):

Protein Expression ◽

Direct Sequencing ◽

Carney Complex ◽

Tumor Formation ◽

Odontogenic Tumors ◽

Maxillary Bone ◽

Synonymous Mutations ◽

Show Evidence ◽

Molecular Therapies ◽

Mixed Odontogenic Tumors

The surgical treatment of some odontogenic tumors often leads to tooth and maxillary bone loss as well as to facial deformity. Therefore, the identification of genes involved in the pathogenesis of odontogenic tumors may result in alternative molecular therapies. ThePRKAR1Agene displays a loss of protein expression as well as somatic mutations in odontogenic myxomas, an odontogenic ectomesenchymal neoplasm. We used a combination of quantitative RT-PCR (qRT-PCR), immunohistochemistry, loss of heterozygosity (LOH) analysis, and direct sequencing of allPRKAR1Aexons to assess if this gene is altered in mixed odontogenic tumors. Thirteen tumors were included in the study: six ameloblastic fibromas, four ameloblastic fibro-odontomas, one ameloblastic fibrodentinoma, and two ameloblastic fibrosarcomas. The epithelial components of the tumors were separated from the mesenchymal by laser microdissection in most of the cases. We also searched for odontogenic pathology inPrkar1a+/−mice.PRKAR1AmRNA/protein expression was decreased in the benign mixed odontogenic tumors in association with LOH at markers around thePRKAR1Agene. We also detected a missense and two synonymous mutations along with two 5′-UTR and four intronic mutations in mixed odontogenic tumors.Prkar1a+/−mice did not show evidence of odontogenic tumor formation, which indicates that additional genes may be involved in the pathogenesis of such tumors, at least in rodents. We conclude that thePRKAR1Agene and its locus are altered in mixed odontogenic tumors.PRKAR1Aexpression is decreased in a subset of tumors but not in all, andPrkar1a+/−mice do not show abnormalities, which indicates that additional genes play a role in this tumor's pathogenesis.

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

Clinical Science ◽

10.1042/cs20070430 ◽

2008 ◽

Vol 115 (7) ◽

pp. 203-218 ◽

Cited By ~ 262

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.

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ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance

International Journal of Molecular Sciences ◽

10.3390/ijms20174153 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4153 ◽

Cited By ~ 2

Author(s):

Giovanna Capolongo ◽

Yoko Suzumoto ◽

Mariavittoria D’Acierno ◽

Mariadelina Simeoni ◽

Giovambattista Capasso ◽

...

Keyword(s):

Protein Kinases ◽

Mapk Signaling ◽

Signalling Pathway ◽

Renal Diseases ◽

Cellular Functions ◽

Acid Base ◽

Mapk Activity ◽

Extracellular Signal ◽

Wide Range ◽

Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

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Hautalterung: Über die Rolle von Fibroblasten-Wachstumsfaktoren

Karger Kompass Dermatologie ◽

10.1159/000507002 ◽

2020 ◽

Vol 8 (2) ◽

pp. 65-67

Author(s):

Andrea Schulz

Keyword(s):

Map Kinases ◽

Skin Resistance ◽

Skin Aging ◽

Mitogen Activated Protein Kinase ◽

Cellular Functions ◽

Molecular Alterations ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Relevant Role ◽

Dermal Cells

Cutaneous aging is a complex and continuous biological process characterized by cellular and molecular alterations, with progressive reduction of the bodyʼs capacity to maintain the homeostasis, senescence, and/or apoptosis of the dermal cells. Fibroblast growth factors (FGF) have elicited studies to evaluate their role of repair and remodeling of the dermis during the skin anti-aging process, since they are regulatory proteins that mediate important signaling pathways and act on cell regeneration and repair processes. FGF acts primarily through binding to tyrosine kinase receptors through the autophosphorylation of their residues, promoting the phosphorylation of serine, threonine, and tyrosine residues of specific target proteins such as Raf-1, MAPK/Erk kinase, and extracellular signal-regulated kinase-1, which are part of the cascade of MAP kinases (mitogen-activated protein kinase). Then, FGF initiate signaling cascades inside the cell, where each kinase activates the following by phosphorylation, resulting in alterations of cellular functions. In addition, the FGF has a relevant role in anti-aging therapy because it is related to collagen and elastin synthesis activation responsible for skin resistance and elasticity, characteristics that are diminished with skin aging. Thus, the present article aims to review several scientific studies that demonstrated the cell signaling involved with the action of FGF on skin aging.

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

Molecular and Cellular Biology ◽

10.1128/mcb.26.6.2408-2418.2006 ◽

2006 ◽

Vol 26 (6) ◽

pp. 2408-2418 ◽

Cited By ~ 187

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.

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Delivery of Sorafenib and Metformin Against Hepatocellular Carcinoma with Amphiphilic Polypeptide-based Micelles

10.21203/rs.3.rs-944726/v1 ◽

2021 ◽

Author(s):

Lanqing Cao ◽

Guangmeng Xu ◽

Hongyu He ◽

Jiannan Li

Keyword(s):

Mapk Pathway ◽

Synergistic Effects ◽

Mitogen Activated Protein Kinase ◽

High Recurrence Rate ◽

Extracellular Signal Regulated Kinase ◽

Cycle Arrest ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Poly Ethylene

Abstract Hepatoma is a common clinical disease with poor prognosis and a high recurrence rate. Chemotherapy is important for hepatoma treatment because only a small amount of hepatoma patients are suitable for local resection, and the effects of transarterial chemoembolization (TACE) are unsatisfactory. But many limitations restrict further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) micelles were developed. Sor is a common molecular target agent which can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat hepatoma clinically. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against hepatoma. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. Both orthotopic and patient-derived xenograft (PDX) hepatoma models were developed to analyze the treatment efficacy of the Sor and Met loaded micelles. The in vivo study showed that the micelles can prevent hepatoma progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for hepatoma treatment.

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The role of scaffold proteins in MEK/ERK signalling

Biochemical Society Transactions ◽

10.1042/bst0340833 ◽

2006 ◽

Vol 34 (5) ◽

pp. 833-836 ◽

Cited By ~ 49

Author(s):

D.B. Sacks

Keyword(s):

Mammalian Cells ◽

Phorbol Esters ◽

Biological Response ◽

Adaptor Proteins ◽

Scaffold Proteins ◽

Mitogen Activated Protein Kinase ◽

Cellular Functions ◽

Extracellular Signal ◽

Kinase Suppressor Of Ras ◽

Mitogen Activated Protein

Signal transduction networks allow cells to recognize and respond to changes in the extracellular environment. All eukaryotic cells have MAPK (mitogen-activated protein kinase) pathways that participate in diverse cellular functions, including differentiation, survival, transformation and movement. Five distinct groups of MAPKs have been characterized in mammals, the most extensively studied of which is the Ras/Raf/MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]/ERK cascade. Numerous stimuli, including growth factors and phorbol esters, activate MEK/ERK signalling. How disparate extracellular signals are translated by MEK/ERK into different cellular functions remains obscure. Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), β-arrestin, MEK partner-1, Sef and IQGAP1. Scaffolds organize multiprotein signalling complexes. This targets MEK/ERK to specific substrates and facilitates communication with other pathways, thereby mediating diverse functions. The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.

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Distinct roles for extracellular-signal-regulated protein kinase (ERK) mitogen-activated protein kinases and phosphatidylinositol 3-kinase in the regulation of Mcl-1 synthesis

Biochemical Journal ◽

10.1042/bj3560473 ◽

2001 ◽

Vol 356 (2) ◽

pp. 473-480 ◽

Cited By ~ 28

Author(s):

Kathryn M. SCHUBERT ◽

Vincent DURONIO

Keyword(s):

Protein Kinase ◽

Mapk Pathway ◽

Family Members ◽

Protein Translation ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Phosphatidylinositol 3 Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Phosphatidylinositol 3

Alterations in the expression of various Bcl-2 family members may act as one means by which a cell's survival may be regulated. The mechanism by which cytokines regulate expression of Bcl-2 family members was examined in the haemopoietic cell line TF-1. Cytokine-induced Mcl-1 protein expression was shown to be controlled through a pathway dependent upon phosphatidylinositol 3-kinase (PI 3-kinase). The cytokine-induced increase in mRNA transcription was not dependent upon PI 3-kinase, thus dissociating the immediate-early transcription factors responsible for Mcl-1 transcription from the PI 3-kinase signalling pathway. In contrast, Mcl-1 mRNA levels were dependent upon MEK [mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated protein kinase kinase] activation, suggesting a role for the Ras/MEK/MAPK pathway in Mcl-1 transcription. Activation of PI 3-kinase was shown to be necessary to stimulate Mcl-1 protein translation. This was not due to any effect on prolonging the half-life of the protein. Finally, the lipid second messenger ceramide was shown to cause a reduction in Mcl-1 protein translation, probably via its ability to inhibit protein kinase B activation, providing further clues regarding the death-inducing effect of this lipid.

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