scholarly journals Cross Talk between Notch and Growth Factor/Cytokine Signaling Pathways in Neural Stem Cells

2007 ◽  
Vol 27 (11) ◽  
pp. 3982-3994 ◽  
Author(s):  
Motoshi Nagao ◽  
Michiya Sugimori ◽  
Masato Nakafuku
Keyword(s):  
Stem Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Neural Stem Cells ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
The Self ◽  
Cell Surface Receptor ◽  
Cytokine Signaling ◽  
Self Renewal

ABSTRACT Precise control of proliferation and differentiation of multipotent neural stem cells (NSCs) is crucial for proper development of the nervous system. Although signaling through the cell surface receptor Notch has been implicated in many aspects of neural development, its role in NSCs remains elusive. Here we examined how the Notch pathway cross talks with signaling for growth factors and cytokines in controlling the self-renewal and differentiation of NSCs. Both Notch and growth factors were required for active proliferation of NSCs, but each of these signals was sufficient and independent of the other to inhibit differentiation of neurons and glia. Moreover, Notch signals could support the clonal self-renewing growth of NSCs in the absence of growth factors. This growth factor-independent action of Notch involved the regulation of the cell cycle and cell-cell interactions. During differentiation of NSCs, Notch signals promoted the generation of astrocytes in collaboration with ciliary neurotrophic factor and growth factors. Their cooperative actions were likely through synergistic phosphorylation of signal transducer and activator of transcription 3 on tyrosine at position 705 and serine at position 727. Our data suggest that distinct intracellular signaling pathways operate downstream of Notch for the self-renewal of NSCs and stimulation of astrogenesis.

scholarly journals Protein Kinases and Their Inhibitors in Pluripotent Stem Cell Fate Regulation

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jungwoon Lee ◽  
Young-Jun Park ◽  
Haiyoung Jung
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Protein Kinases ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Intracellular Signaling ◽  
Regulatory Networks ◽  
Kinase Signaling ◽  
Self Renewal ◽  
Lineage Differentiation

Protein kinases modulate the reversible postmodifications of substrate proteins to their phosphorylated forms as an essential process in regulating intracellular signaling transduction cascades. Moreover, phosphorylation has recently been shown to tightly control the regulatory network of kinases responsible for the induction and maintenance of pluripotency, defined as the particular ability to differentiate pluripotent stem cells (PSCs) into every cell type in the adult body. In particular, emerging evidence indicates that the balance between the self-renewal and differentiation of PSCs is regulated by the small molecules that modulate kinase signaling pathways. Furthermore, new reprogramming technologies have been developed using kinase modulators, which have provided novel insight of the mechanisms underlying the kinase regulatory networks involved in the generation of induced pluripotent stem cells (iPSCs). In this review, we highlight the recent progress made in defining the roles of protein kinase signaling pathways and their small molecule modulators in regulating the pluripotent states, self-renewal, reprogramming process, and lineage differentiation of PSCs.

Lnk Constrains Oncogenic JAK2-Induced Myeloproliferative Disease in Mice.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1437-1437
Author(s):  
Alexey Bersenev ◽  
Chao Wu ◽  
Joanna Balcerek ◽  
Wei Tong
Keyword(s):  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Adaptor Protein ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Myelogenous Leukemia ◽  
Cell Surface Receptor ◽  
Cytokine Signaling ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 1437 Poster Board I-460 Hematopoietic stem cell (HSC) homeostasis and self-renewal are regulated by intrinsic cytokine signaling pathways. One important signaling axis for HSC is the cell surface receptor, Mpl, and its ligand, thrombopoietin (Tpo). Upon Tpo stimulation, Mpl activates Janus Kinase (JAK2), which in turn triggers a cascade of downstream signal transduction pathways that regulate key aspects of cell development. Mice that lack the inhibitory adaptor protein Lnk harbor a vastly expanded HSC pool with enhanced self-renewal. We previously demonstrated that Lnk controls HSC self-renewal predominantly through the Mpl/JAK2 pathway. Lnk binds directly to phosphorylated tyrosine 813 in JAK2 upon Tpo stimulation. Moreover, Lnk-deficient HSCs display potentiated JAK2 activation. Dysregulation of cytokine receptor signaling pathways frequently lead to hematological malignancies. Abnormal activation of JAK2 by a chromosomal translocation between the transcription factor Tel and JAK2 (Tel/JAK2) was shown to cause atypical Chronic Myelogenous Leukemia (aCML) in human patients. Moreover, the JAK2 V617F mutation has been observed at high frequency in several myeloproliferative diseases (MPDs). The JAK2V617F retains Lnk binding, suggesting that alterations in Lnk could influence MPD development. Indeed, we found that loss of Lnk accelerates and exacerbates oncogenic JAK2-induced MPD in mouse transplant models. Specifically, Lnk deficiency enhanced cytokine signaling, thereby augmenting the ability of oncogenic JAK2 to expand myeloid progenitors. To test whether the interaction between Lnk and JAK2V617F directly constrains MPD development in mice, we transplanted wild-type bone marrow cells expressing the JAK2V617F/Y813F double mutant that does not interact with Lnk (WT;JAK2VF/YF). WT;JAK2VF/YF engrafted mice exhibited increased myeloid expansion when compared to WT;JAK2VF mice, and conferred accelerated polycythemia vera development in secondary transplants. In summary, we identified Lnk as a physiological negative regulator of JAK2 in stem cells that may constrain leukemic transformation conferred by oncogenic JAK2. Disclosures No relevant conflicts of interest to declare.

scholarly journals The bHLH Repressor Deadpan Regulates the Self-renewal and Specification of Drosophila Larval Neural Stem Cells Independently of Notch

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e46724 ◽  
Author(s):  
Sijun Zhu ◽  
Jill Wildonger ◽  
Suzanne Barshow ◽  
Susan Younger ◽  
Yaling Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
The Self ◽  
Self Renewal

scholarly journals Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies

2021 ◽  
Vol 11 ◽  
Author(s):  
Thahomina Khan ◽  
Horacio Cabral
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Self Renewal ◽  
Tumor Relapse ◽  
Intracellular Signaling Pathways ◽  
Abnormal Glycosylation

Cancer stem cell (CSCs) are deemed as one of the main reasons of tumor relapse due to their resistance to standard therapies. Numerous intracellular signaling pathways along with extracellular features are crucial in regulating CSCs properties, such as heterogeneity, plasticity and differentiation. Aberrant glycosylation of these cellular signaling pathways and markers of CSCs have been directly correlated with maintaining survival, self-renewal and extravasation properties. In this review, we highlight the importance of glycosylation in promoting stemness character of CSCs, and present strategies for targeting abnormal glycosylation to eliminate the resistant CSC population.

scholarly journals Glycoprotein 130 Signaling RegulatesNotch1Expression and Activation in the Self-Renewal of Mammalian Forebrain Neural Stem Cells

2003 ◽  
Vol 23 (5) ◽  
pp. 1730-1741 ◽  
Author(s):  
Andrew Chojnacki ◽  
Takuya Shimazaki ◽  
Christopher Gregg ◽  
Gerry Weinmaster ◽  
Samuel Weiss
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
The Self ◽  
Self Renewal

PDGF, TGF-β, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 295-307 ◽  
Author(s):  
Felicia Ng ◽  
Shayne Boucher ◽  
Susie Koh ◽  
Konduru S. R. Sastry ◽  
Lucas Chase ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Transcriptional Profiling ◽  
Global Gene Expression ◽  
Cell Surface Receptor ◽  
Fgf Signaling ◽  
Global Gene Expression Profiling

Abstract We compared the transcriptomes of marrow-derived mesenchymal stem cells (MSCs) with differentiated adipocytes, osteocytes, and chondrocytes derived from these MSCs. Using global gene-expression profiling arrays to detect RNA transcripts, we have identified markers that are specific for MSCs and their differentiated progeny. Further, we have also identified pathways that MSCs use to differentiate into adipogenic, chondrogenic, and osteogenic lineages. We identified activin-mediated transforming growth factor (TGF)–β signaling, platelet-derived growth factor (PDGF) signaling and fibroblast growth factor (FGF) signaling as the key pathways involved in MSC differentiation. The differentiation of MSCs into these lineages is affected when these pathways are perturbed by inhibitors of cell surface receptor function. Since growth and differentiation are tightly linked processes, we also examined the importance of these 3 pathways in MSC growth. These 3 pathways were necessary and sufficient for MSC growth. Inhibiting any of these pathways slowed MSC growth, whereas a combination of TGF-β, PDGF, and β-FGF was sufficient to grow MSCs in a serum-free medium up to 5 passages. Thus, this study illustrates it is possible to predict signaling pathways active in cellular differentiation and growth using microarray data and experimentally verify these predictions.

scholarly journals Transcriptional factor FoxM1-activated microRNA-335-3p maintains the self-renewal of neural stem cells by inhibiting p53 signaling pathway via Fmr1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiaoying Jia ◽  
Yan Cui ◽  
Zhigang Tan ◽  
Min Liu ◽  
Yugang Jiang
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Signaling Pathway ◽  
Neurological Diseases ◽  
The Self ◽  
Self Renewal ◽  
P53 Signaling ◽  
Non Coding Rna ◽  
Fetal Rats ◽  
P53 Signaling Pathway

Abstract Background New mechanistic insights into the self-renewal ability and multipotent properties of neural stem cells (NSCs) are currently under active investigation for potential use in the treatment of neurological diseases. In this study, NSCs were isolated from the forebrain of fetal rats and cultured to induce NSC differentiation, which was associated with low expression of the non-coding RNA microRNA-335-3p (miR-335-3p). Methods Loss- and gain-of-function experiments were performed in NSCs after induction of differentiation. Results Overexpression of miR-335-3p or FoxM1 and inhibition of the Fmr1 or p53 signaling pathways facilitated neurosphere formation, enhanced proliferation and cell cycle entry of NSCs, but restricted NSC differentiation. Mechanistically, FoxM1 positively regulated miR-335-3p by binding to its promoter region, while miR-335-3p targeted and negatively regulated Fmr1. Additionally, the promotive effect of miR-335-3p on NSC self-renewal occurred via p53 signaling pathway inactivation. Conclusion Taken together, miR-335-3p activated by FoxM1 could suppress NSC differentiation and promote NSC self-renewal by inactivating the p53 signaling pathway via Fmr1.

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