scholarly journals c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways

2004 ◽  
Vol 24 (3) ◽  
pp. 1401-1410 ◽  
Author(s):  
Li Hong ◽  
Veerendra Munugalavadla ◽  
Reuben Kapur
Keyword(s):  
Signaling Pathways ◽  
Binding Sites ◽  
Cellular Proliferation ◽  
Critical Issue ◽  
Cellular Growth ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Signaling ◽  
Kit Receptor ◽  
And Migration ◽  
The Individual

ABSTRACT A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-γ had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.

Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

2020 ◽  
Vol 26 (15) ◽  
pp. 1729-1741 ◽  
Author(s):  
Seyed H. Shahcheraghi ◽  
Venant Tchokonte-Nana ◽  
Marzieh Lotfi ◽  
Malihe Lotfi ◽  
Ahmad Ghorbani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Chemotherapy Resistance ◽  
Wnt Signaling Pathway ◽  
Therapeutic Interventions ◽  
Beta Catenin ◽  
Clinical Prognosis ◽  
Invasion And Migration ◽  
And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

scholarly journals Interleukin-22: a potential therapeutic target in atherosclerosis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jin-Wen Luo ◽  
Yuan Hu ◽  
Jian Liu ◽  
Huan Yang ◽  
Peng Huang
Keyword(s):  
Signaling Pathways ◽  
Therapeutic Target ◽  
Cholesterol Metabolism ◽  
Inflammatory Diseases ◽  
Vascular Wall ◽  
Main Body ◽  
Vsmc Proliferation ◽  
Downstream Signaling ◽  
Interleukin 22 ◽  
And Migration

Abstract Background Atherosclerosis is recognized as a chronic immuno-inflammatory disease that is characterized by the accumulation of immune cells and lipids in the vascular wall. In this review, we focus on the latest advance regarding the regulation and signaling pathways of IL-22 and highlight its impacts on atherosclerosis. Main body IL-22, an important member of the IL-10 family of cytokines, is released by cells of the adaptive and innate immune system and plays a key role in the development of inflammatory diseases. The binding of IL-22 to its receptor complex can trigger a diverse array of downstream signaling pathways, in particular the JAK/STAT, to induce the expression of chemokines and proinflammatory cytokines. Recently, numerous studies suggest that IL-22 is involved in the pathogenesis of atherosclerosis by regulation of VSMC proliferation and migration, angiogenesis, inflammatory response, hypertension, and cholesterol metabolism. Conclusion IL-22 promotes the development of atherosclerosis by multiple mechanisms, which may be a promising therapeutic target in the pathogenesis of atherosclerosis.

ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways

1998 ◽  
Vol 275 (4) ◽  
pp. H1209-H1215 ◽  
Author(s):  
Peter A. Wilden ◽  
Yehenew M. Agazie ◽  
Rebecca Kaufman ◽  
Stephen P. Halenda
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathways ◽  
Cellular Proliferation ◽  
Muscle Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Mitogen Activated Protein

Vascular smooth muscle cells respond to the purinergic agonist ATP by increasing intracellular calcium concentration and increasing the rate of cell proliferation. In many cells the extracellular signal-regulated kinase (ERK) cascade plays an important role in cellular proliferation. We have studied the effect of extracellular ATP on ERK activation and cell proliferation. ATP binding to a UTP-sensitive P2Y nucleotide receptor activates ERK1/ERK2 in a time- and dose-dependent manner in coronary artery smooth muscle cells (CASMC). ATP-induced activation of ERK1/ERK2 is dependent on the dual-specificity kinase mitogen-activated protein kinase/ERK kinase (i.e., MEK) but independent of phosphatidylinositol 3-kinase (PI3K) activity. We provide evidence that both ERK1/ERK2 and PI3K activities are required for CASMC proliferation. Thus ATP-stimulation of CASMC proliferation requires independent activation of both the ERK and PI3K signaling pathways.

scholarly journals Helicobacter pylori-Mediated Immunity and Signaling Transduction in Gastric Cancer

2020 ◽  
Vol 9 (11) ◽  
pp. 3699
Author(s):  
Nozomi Ito ◽  
Hironori Tsujimoto ◽  
Hideki Ueno ◽  
Qian Xie ◽  
Nariyoshi Shinomiya
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Cellular Proliferation ◽  
Gastric Cancer Cells ◽  
Downstream Signaling ◽  
H Pylori

Helicobacter pylori infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during H. pylori infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon H. pylori stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, H. pylori LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. H. pylori infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in H. pylori infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.

scholarly journals Insights Into Signaling in Cell-Based Therapy for Heart Disease

2017 ◽  
Vol 6 ◽  
pp. 117864341771768
Author(s):  
Angela C Rieger ◽  
Bryon A Tompkins ◽  
Monisha Banerjee ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Heart Disease ◽  
Signaling Pathways ◽  
Cardiac Disease ◽  
Cell Contact ◽  
Downstream Signaling ◽  
Cell Based Therapy ◽  
And Migration ◽  
And Function ◽  
Proliferation And Migration

Over the past several decades, stem cell therapy for heart disease has been translated from the bench to the bedside and in clinical trials improves cardiac structure and function in both ischemic and nonischemic cardiac disease. Although the regenerative effects of stem cells in cardiac disease are mediated by both paracrine and cell-to-cell contact mechanisms, many of the downstream signaling pathways remain to be fully elucidated. This review outlines what is currently known about the main signaling pathways involved in mesenchymal stem cell and cardiac stem cell survival, proliferation, and migration and mechanisms of action to repair the damaged heart.

scholarly journals FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching

2020 ◽  
Vol 13 (621) ◽  
pp. eaay4353 ◽  
Author(s):  
Yongjun Yin ◽  
David M. Ornitz
Keyword(s):  
Signaling Pathways ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Signaling ◽  
Epithelial Development ◽  
Lung Epithelial ◽  
Proliferation And Differentiation ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Pseudoglandular Stage

Fibroblast growth factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelium-produced FGF9 is principally responsible for mesenchymal growth, whereas epithelium-produced FGF9 and mesenchyme-produced FGF10 guide lung epithelial development, and loss of either of these ligands affects epithelial branching. Because FGF9 and FGF10 activate distinct FGF receptors (FGFRs), we hypothesized that they would control distinct developmental processes. Here, we found that FGF9 signaled through epithelial FGFR3 to directly promote distal epithelial fate specification and inhibit epithelial differentiation. By contrast, FGF10 signaled through epithelial FGFR2b to promote epithelial proliferation and differentiation. Furthermore, FGF9-FGFR3 signaling functionally opposed FGF10-FGFR2b signaling, and FGFR3 preferentially used downstream phosphoinositide 3-kinase (PI3K) pathways, whereas FGFR2b relied on downstream mitogen-activated protein kinase (MAPK) pathways. These data demonstrate that, within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct distinct developmental functions through the activation of distinct downstream signaling pathways.

scholarly journals Crosstalk between the Ras2p-controlled Mitogen-activated Protein Kinase and cAMP Pathways during Invasive Growth ofSaccharomyces cerevisiae

1999 ◽  
Vol 10 (5) ◽  
pp. 1325-1335 ◽  
Author(s):  
Hans-Ulrich Mösch ◽  
Eric Kübler ◽  
Sven Krappmann ◽  
Gerald R. Fink ◽  
Gerhard H. Braus
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Invasive Growth ◽  
Interaction Domain ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mutant Proteins ◽  
Downstream Signaling ◽  
Ras Genes

The two highly conserved RAS genes of the budding yeast Saccharomyces cerevisiae are redundant for viability. Here we show that haploid invasive growth development depends on RAS2 but not RAS1. Ras1p is not sufficiently expressed to induce invasive growth. Ras2p activates invasive growth using either of two downstream signaling pathways, the filamentation MAPK (Cdc42p/Ste20p/MAPK) cascade or the cAMP-dependent protein kinase (Cyr1p/cAMP/PKA) pathway. This signal branch point can be uncoupled in cells expressing Ras2p mutant proteins that carry amino acid substitutions in the adenylyl cyclase interaction domain and therefore activate invasive growth solely dependent on the MAPK cascade. Both Ras2p-controlled signaling pathways stimulate expression of the filamentation response element-driven reporter gene depending on the transcription factors Ste12p and Tec1p, indicating a crosstalk between the MAPK and the cAMP signaling pathways in haploid cells during invasive growth.

Regulation of mouse primordial follicle formation by signaling through the PI3K pathway

2021 ◽  
Author(s):  
Joshua J N Burton ◽  
Amanda J Luke ◽  
Melissa E Pepling
Keyword(s):  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Mek Inhibitor ◽  
Pi3k Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Oocyte Growth ◽  
Pi3k Inhibitor Ly294002 ◽  
Downstream Signaling ◽  
Mitogen Activated Protein ◽  
And Migration

Abstract Cell signaling mediated by the KIT receptor is critical for many aspects of oogenesis including the proliferation and migration of primordial germ cells, as well as the survival, growth, and maturation of ovarian follicles. We previously showed that KIT regulates cyst breakdown and primordial follicle formation, and in this study, have investigated the mechanisms downstream of the receptor by modulating the activity of two downstream signaling cascades: the phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways. E17.5 ovaries were cultured for five days with a daily dose of media supplemented with either the PI3K inhibitor LY294002, the MEK inhibitor U0126, or a DMSO vehicle control. Our histological observations aligned with the established role of PI3K in oocyte growth and primordial follicle activation but also revealed that LY294002 treatment delayed the processes of cyst breakdown and primordial follicle formation. U0126 treatment also led to a reduction in oocyte growth and follicle development but did not appear to affect cyst breakdown. The delay in cyst breakdown was mitigated when ovaries were dually dosed with LY294002 and KITL, suggesting that while KIT may signal through PI3K to promote cyst breakdown, other signaling networks downstream of the receptor could compensate. These observations unearth a role for PI3K signaling in the establishment of the ovarian reserve and suggest that PI3K might be the primary mediator of KIT-induced cyst breakdown and primordial follicle formation in the mouse ovary.

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4039-4047 ◽  
Author(s):  
Clotilde Simon ◽  
Elisabetta Dondi ◽  
Amandine Chaix ◽  
Paulo de Sepulveda ◽  
Terrance J. Kubiseski ◽  
...  
Keyword(s):  
Mast Cells ◽  
Signaling Pathways ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Inhibitory Function ◽  
Mitogen Activated Protein ◽  
And Migration ◽  
Carboxy Terminal

Abstract Stem cell factor (SCF) plays critical roles in proliferation, survival, migration, and function of hematopoietic progenitor and mast cells through binding to Kit receptor. Previous studies have implicated the adaptor protein Lnk as an important negative regulator of SCF signaling. However, the molecular mechanism underlying this regulation is unclear. Here, we showed that the Src homology 2 domain (SH2) of Lnk binds directly and preferentially to phosphorylated tyrosine 567 in Kit juxtamembrane domain. Using Lnk−/− bone marrow mast cells (BMMCs) transduced with different Lnk proteins, we demonstrated that Lnk down-regulates SCF-induced proliferation with attenuation of mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase signaling. Furthermore, we showed that Lnk−/− BMMCs displayed increased SCF-dependent migration compared with wild-type cells, revealing a novel Lnk-mediated inhibitory function. This correlated with enhanced Rac and p38 MAPK activation. Finally, we found that Lnk domains and carboxy-terminal tyrosine contribute differently to inhibition of in vitro expansion of hematopoietic progenitors. Altogether, our results demonstrate that Lnk, through its binding to Kit tyrosine 567, negatively modulates specific SCF-dependent signaling pathways involved in the proliferation and migration of primary hematopoietic cells.

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