scholarly journals RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

2015 ◽  
Vol 35 (10) ◽  
pp. 1673-1685 ◽  
Author(s):  
Hetian Lei ◽  
Cynthia X. Qian ◽  
Jinghu Lei ◽  
Luis J. Haddock ◽  
Shizuo Mukai ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor Receptor ◽  
Cellular Responses ◽  
Underlying Mechanism ◽  
Platelet Derived Growth Factor ◽  
Eye Disease ◽  
Oxygen Species ◽  
Gtpase Activating Protein ◽  
Indirect Activation

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) make profound contributions to both physiology and pathology. While it is widely believed that direct (PDGF-mediated) activation is the primary mode of activating PDGFRs, the discovery that they can also be activated indirectly begs the question of the relevance of the indirect mode of activating PDGFRs. In the context of a blinding eye disease, indirect activation of PDGFRα results in persistent signaling, which suppresses the level of p53 and thereby promotes viability of cells that drive pathogenesis. Under the same conditions, PDGFRβ fails to undergo indirect activation. In this paper, we report that RasGAP (GTPase-activating protein of Ras) prevented indirect activation of PDGFRβ. RasGAP, which associates with PDGFRβ but not PDGFRα, reduced the level of mitochondrion-derived reactive oxygen species, which are required for enduring activation of PDGFRs. Furthermore, preventing PDGFRβ from associating with RasGAP allowed it to signal enduringly and drive pathogenesis of a blinding eye disease. These results indicate a previously unappreciated role of RasGAP in antagonizing indirect activation of PDGFRβ, define the underlying mechanism, and raise the possibility that PDGFRβ-mediated diseases involve indirect activation of PDGFRβ.

scholarly journals Upregulation of TLR1, TLR2, TLR4, and IRAK-2 Expression During ML-1 Cell Differentiation to Macrophages: Role in the Potentiation of Cellular Responses to LPS and LTA

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Kassim Traore ◽  
Barry Zirkin ◽  
Rajesh K. Thimmulappa ◽  
Shyam Biswal ◽  
Michael A. Trush
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Cell Differentiation ◽  
Inflammatory Cytokines ◽  
Cellular Responses ◽  
Signaling Cascade ◽  
Oxygen Species ◽  
Induced Differentiation ◽  
Protein Levels

12-O-tetradecanoylphorbol 13-acetate (TPA) induces the differentiation of human myeloid ML-1 cells to macrophages. In the current study, the expression, responsiveness, and regulation of toll-like receptors (TLRs) in TPA-induced ML-1-derived macrophages were investigated. We have found that TPA-induced differentiation of ML-1 cells was accompanied by the upregulation of TLR1, TLR2, TLR4, and CD14 expression at both the mRNA and protein levels. Interestingly, TLR1 and TLR4 protein expression on ML-1 cells could be blocked by pretreatment with U0126, suggesting the role of an Erk1/2-induced differentiation signal in this process. In addition, the expression of IRAK-2, a key member of the TLR/IRAK-2/NF-κB-dependent signaling cascade was also induced in response to TPA. Accordingly, we demonstrated an increased cellular release of inflammatory cytokines (TNF-α and various interleukins) upon stimulation with LPS and LTA ligands for TLR4 and TLR2, respectively. Furthermore, using luminol-dependent chemiluminescence, addition of LPS and LTA induces a sustained DPI-inhibitable generation of reactive oxygen species (ROS) by the differentiated ML-1 cells. Together, these data suggest that the increase in the responsiveness of TPA-treated ML-1 cells to LPS and LTA occurs in response to the upregulation of their respective receptors as well as an induction of the IRAK-2 gene expression.

scholarly journals GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

2019 ◽  
Vol 1 (1) ◽  
pp. R1-R11 ◽  
Author(s):  
Raafat Mohamed ◽  
Reearna Janke ◽  
Wanru Guo ◽  
Yingnan Cao ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor ◽  
Drug Targets ◽  
Protein Tyrosine Kinase ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Reactive Oxygen ◽  
Transforming Growth Factor Β ◽  
Oxygen Species

The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

scholarly journals Hypoxic Pulmonary Vasoconstriction in Humans: Tale or Myth

2017 ◽  
Vol 11 (1) ◽  
pp. 1-13 ◽  
Author(s):  
A. Hussain ◽  
M.S. Suleiman ◽  
S.J. George ◽  
M. Loubani ◽  
A. Morice
Keyword(s):  
Reactive Oxygen Species ◽  
Rho Gtpases ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Underlying Mechanism ◽  
Clinical Implications ◽  
Oxygen Species ◽  
Adaptive Process ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasoconstriction

Hypoxic Pulmonary vasoconstriction (HPV) describes the physiological adaptive process of lungs to preserves systemic oxygenation. It has clinical implications in the development of pulmonary hypertension which impacts on outcomes of patients undergoing cardiothoracic surgery. This review examines both acute and chronic hypoxic vasoconstriction focusing on the distinct clinical implications and highlights the role of calcium and mitochondria in acute versus the role of reactive oxygen species and Rho GTPases in chronic HPV. Furthermore it identifies gaps of knowledge and need for further research in humans to clearly define this phenomenon and the underlying mechanism.

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