scholarly journals Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 465 ◽  
Author(s):  
Manfred Kunz ◽  
Julio Vera
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Strong Dependence ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Single Chain ◽  
Network Modelling

Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitogen-activated protein kinase (MAPK) MAP2K1 (also termed MEK1) have improved overall survival of melanoma patients. However, the MAPK signaling pathway is far more complex than a single chain of consecutively activated MAPK enzymes and it contains nested-, inherent feedback mechanisms, crosstalk with other signaling pathways, epigenetic regulatory mechanisms, and interacting small non-coding RNAs. A more complete understanding of this pathway is needed to better understand melanoma development and mechanisms of treatment resistance. Network reconstruction, analysis, and modelling under the systems biology paradigm have been used recently in different malignant tumors including melanoma to analyze and integrate ‘omics’ data, formulate mechanistic hypotheses on tumorigenesis, assess and personalize anticancer therapy, and propose new drug targets. Here we review the current knowledge of network modelling approaches in cancer with a special emphasis on melanoma.

scholarly journals TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii

2004 ◽  
Vol 72 (10) ◽  
pp. 5662-5667 ◽  
Author(s):  
Nicola J. Mason ◽  
Jim Fiore ◽  
Takashi Kobayashi ◽  
Katherine S. Masek ◽  
Yongwon Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Wild Type ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-κB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-κB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-κB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6−/− mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6−/− mice failed to produce IL-12(p40) in response to STAg, and TRAF6−/− macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6−/− macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

scholarly journals Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1198
Author(s):  
Sathishbabu Paranthaman ◽  
Meghana Goravinahalli Shivananjegowda ◽  
Manohar Mahadev ◽  
Afrasim Moin ◽  
Shivakumar Hagalavadi Nanjappa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Surface ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Extensive Literature ◽  
Egfr Tkis

A paradigm shift in treating the most aggressive and malignant form of glioma is continuously evolving; however, these strategies do not provide a better life and survival index. Currently, neurosurgical debulking, radiotherapy, and chemotherapy are the treatment options available for glioma, but these are non-specific in action. Patients invariably develop resistance to these therapies, leading to recurrence and death. Receptor Tyrosine Kinases (RTKs) are among the most common cell surface proteins in glioma and play a significant role in malignant progression; thus, these are currently being explored as therapeutic targets. RTKs belong to the family of cell surface receptors that are activated by ligands which in turn activates two major downstream signaling pathways via Rapidly Accelerating Sarcoma/mitogen activated protein kinase/extracellular-signal-regulated kinase (Ras/MAPK/ERK) and phosphatidylinositol 3-kinase/a serine/threonine protein kinase/mammalian target of rapamycin (PI3K/AKT/mTOR). These pathways are critically involved in regulating cell proliferation, invasion, metabolism, autophagy, and apoptosis. Dysregulation in these pathways results in uncontrolled glioma cell proliferation, invasion, angiogenesis, and cancer progression. Thus, RTK pathways are considered a potential target in glioma management. This review summarizes the possible risk factors involved in the growth of glioblastoma (GBM). The role of RTKs inhibitors (TKIs) and the intracellular signaling pathways involved, small molecules under clinical trials, and the updates were discussed. We have also compiled information on the outcomes from the various endothelial growth factor receptor (EGFR)–TKIs-based nanoformulations from the preclinical and clinical points of view. Aided by an extensive literature search, we propose the challenges and potential opportunities for future research on EGFR–TKIs-based nanodelivery systems.

scholarly journals Melanogenic Effects of Maclurin Are Mediated through the Activation of cAMP/PKA/CREB and p38 MAPK/CREB Signaling Pathways

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Young Sun Hwang ◽  
Sae Woong Oh ◽  
See-Hyoung Park ◽  
Jienny Lee ◽  
Ju Ah. Yoo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Adenosine Monophosphate ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Protective Agent ◽  
Protective Effects ◽  
Skin Disorders ◽  
Creb Phosphorylation

Melanogenesis is the biological process which the skin pigment melanin is synthesized to protect the skin against ultraviolet irradiation and other external stresses. Abnormal biology of melanocytes is closely associated with depigmented skin disorders such as vitiligo. In this study, we examined the effects of maclurin on melanogenesis and cytoprotection. Maclurin enhanced cellular tyrosinase activity as well as cellular melanin levels. We found that maclurin treatment increased the expression of microphthalmia-associated transcription factor (MITF), tyrosinase-related protein- (TRP-) 1, TRP-2, and tyrosinase. Mechanistically, maclurin promoted melanogenesis through cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein-dependent upregulation of MITF. CREB activation was found to be mediated by p38 mitogen-activated protein kinase (MAPK) or cAMP-protein kinase A (PKA) signaling. In addition, maclurin-induced CREB phosphorylation was mediated through the activation of both the cAMP/PKA and the p38 MAPK signaling pathways. Maclurin-induced suppression of p44/42 MAPK activation also contributed to its melanogenic activity. Furthermore, maclurin showed protective effects against H2O2 treatment and UVB irradiation in human melanocytes. These findings indicate that the melanogenic effects of maclurin depend on increased MITF gene expression, which is mediated by the activation of both p38 MAPK/CREB and cAMP/PKA/CREB signaling. Our results thus suggest that maclurin could be useful as a protective agent against hypopigmented skin disorders.

scholarly journals Role of Mitogen- and Stress-Activated Kinases in Ischemic Injury

2002 ◽  
Vol 22 (6) ◽  
pp. 631-647 ◽  
Author(s):  
Elaine A. Irving ◽  
Mark Bamford
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Focal Cerebral Ischemia ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Amino Terminal ◽  
Biological Responses ◽  
Mitogen Activated Protein

Protein kinase-mediated signaling cascades constitute the major route by which cells respond to their extracellular environment. Of these, three well-characterized mitogen-activated protein kinase (MAPK) signaling pathways are those that use the extracellular signal-regulated kinase (ERK1/2) or the stress-activated protein kinase (p38/SAPK2 or JNK/SAPK) pathways. Mitogenic stimulation of the MAPK-ERK1/2 pathway modulates the activity of many transcription factors, leading to biological responses such as proliferation and differentiation. In contrast, the p38/SAPK2 and JNK/SAPK (c-Jun amino-terminal kinase/stress-activated protein kinase) pathways are only weakly, if at all, activated by mitogens, but are strongly activated by stress stimuli. There is now a growing body of evidence showing that these kinase signaling pathways become activated following a variety of injury stimuli including focal cerebral ischemia. Whether their activation, however, is merely an epiphenomenon of the process of cell death, or is actually involved in the mechanisms underlying ischemia-induced degeneration, remains to be fully understood. This review provides an overview of the current understanding of kinase pathway activation following cerebral ischemia and discusses the evidence supporting a role for these kinases in the mechanisms underlying ischemia-induced cell death.

scholarly journals Parallel Phosphatidylinositol-3 Kinase and p42/44 Mitogen-Activated Protein Kinase Signaling Pathways Subserve the Mitogenic and Antiapoptotic Actions of Insulin-Like Growth Factor I in Osteoblastic Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (11) ◽  
pp. 4886-4893 ◽  
Author(s):  
Andrew Grey ◽  
Qi Chen ◽  
Xin Xu ◽  
Karen Callon ◽  
Jill Cornish
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Osteoblastic Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
P70s6 Kinase ◽  
Igf I ◽  
Convergence Point ◽  
Phosphatidylinositol 3

Abstract IGF-I is an endocrine and paracrine regulator of skeletal homeostasis, principally by virtue of its anabolic effects on osteoblastic cells. In the current study, we examined the intracellular signaling pathways by which IGF-I promotes proliferation and survival in SaOS-2 human osteoblastic cells. Inhibition of each of the phosphatidylinositol-3 kinase (PI-3 kinase), p42/44 MAPK, and p70s6 kinase pathways partially inhibited the ability of IGF-I to stimulate osteoblast proliferation and survival. Because activation of p70s6 kinase is downstream of both PI-3 kinase and p42/44 MAPK activation in osteoblasts treated with IGF-I, this ribosomal kinase represents a convergence point for IGF-I-induced PI-3 kinase and p42/44 MAPK signaling in osteoblastic cells. In addition, abrogation of PI-3 kinase-dependent Akt signaling, which does not inhibit IGF-I-induced p70s6 kinase phosphorylation, also inhibited the antiapoptotic effects of IGF-I in osteoblasts. Finally, interruption of Gβγ signaling partially abrogated the ability of IGF-I to promote osteoblast survival, without inhibiting signaling through PI-3 kinase/Akt, p42/44 MAPKs, or p70s6 kinase. These data suggest that IGF-I signals osteoblast mitogenesis and survival through parallel, partly overlapping intracellular pathways involving PI-3 kinase, p42/44 MAPKs, and Gβγ subunits.

Panax notoginseng Saponins Modulate the Inflammatory Response and Improve IBD-Like Symptoms via TLR/NF-κB and MAPK Signaling Pathways

2021 ◽  
pp. 1-15
Author(s):  
Hua Luo ◽  
Chi Teng Vong ◽  
Dechao Tan ◽  
Jinming Zhang ◽  
Hua Yu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Panax Notoginseng ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Clinical Effects ◽  
Protective Effects ◽  
Panax Notoginseng Saponins

Panax notoginseng saponins (PNS) are the main active ingredients of Panax notoginseng (Burk) F. H. Chen, which are used as traditional Chinese medicine for thousands of years and have various clinical effects, including anti-inflammation, anti-oxidation, and cardiovascular protection. Inflammatory bowel disease (IBD) is a complex gastrointestinal inflammatory disease that cannot be cured completely nowadays. The anti-inflammatory and protective effects of PNS were analyzed in vitro and in dextran sulfate sodium (DSS)-induced colitis mouse model. PNS inhibited the release of nitric oxide (NO), tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in Pam3CSK4-induced RAW 264.7 macrophages. In the animal study, compared with DSS-induced mice, PNS reduced the expression of pro-inflammatory cytokines (TNF-[Formula: see text], IL-6, and MCP-1) in the colon tissues. Furthermore, PNS treatment led to a remarkable reduction in the activation of the inhibitor of nuclear factor kappa-B kinase [Formula: see text]/[Formula: see text] (IKK[Formula: see text]/[Formula: see text], I[Formula: see text]B[Formula: see text] and p65 induced by DSS. On the other hand, PNS inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular regulated protein kinase 1/2 (ERK1/2). Taken together, our results suggested that PNS conferred profound protection for colitis mice through the downregulation of mitogen-activated protein kinase (MAPK) and NF-[Formula: see text]B signaling pathways, which were associated with reducing inflammatory responses, alleviating tissue damage, and maintaining of intestinal integrity and functionality.

Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2175-2182 ◽  
Author(s):  
Amaya Puig-Kröger ◽  
Miguel Relloso ◽  
Oskar Fernández-Capetillo ◽  
Ana Zubiaga ◽  
Augusto Silva ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Mannose Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Functional Maturation ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Mitogen Activated Protein

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor α [TNF-α] and interleukin-1β [IL-1β]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1–extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-α– and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor–mediated endocytic activity; nuclear factor-κB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-α. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.

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