• Archives of Pharmacal Research
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• 제21권5호
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• pp.487-495
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• 1998

Gorwth factors such as TGF-beta, PDGF and FGF are thought to play important roles in wound healing. However, thier biological activity and signal transduction during wound repair remain poorly understood. Growth factors are often ligands for receptor tyrosine kinase and receptor serine/threonine kinases. With recent advances in signal transduction by receptor kinases, we are beginning to understand the underlying mechanism of how growth factors may regulate cutaneous wound repair. In this paper, we will describe the pharmacological effects of growth factors on wound healing, and dscuss the potential underlying signaing mechanisms. thus, we hope to provide the basis for designing more specific therapeutics for wound healing in the near future.

• Molecules and Cells
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• 제42권1호
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• pp.1-7
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• 2019

Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.

• Molecules and Cells
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• 제26권4호
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• pp.329-337
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• 2008

Src-family kinases are critically involved in the control of cytoskeleton organization and in the generation of integrin-dependent signaling responses, inducing tyrosine phosphorylation of many signaling and cytoskeletal proteins. Activity of the Src family of tyrosine kinases is tightly controlled by inhibitory phosphorylation of a carboxy-terminal tyrosine residue, inducing an inactive conformation through binding with its SH2 domain. Dephosphorylation of C-ter tyrosine, as well as its deletion of substitution with phenylalanine in oncogenic Src kinases, leads to autophosphorylation at a tyrosine in the activation loop, thereby leading to enhanced Src activity. Beside this phophorylation/dephosphorylation circuitry, cysteine oxidation has been recently reported as a further mechanism of enzyme activation. Mounting evidence describes Src activation via its redox regulation as a key outcome in several circumstances, including growth factor and cytokines signaling, integrin-mediated cell adhesion and motility, membrane receptor cross-talk as well in cell transformation and tumor progression. Among the plethora of data involving Src kinase in physiological and pathophysiological processes, this review will give emphasis to the redox component of the regulation of this master kinase.

• Tuberculosis and Respiratory Diseases
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• 제75권5호
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• pp.188-198
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• 2013

Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.

• Natural Product Sciences
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• 제27권3호
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• pp.216-216
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• 2021

• 한국컴퓨터정보학회논문지
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• 제21권9호
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• pp.101-106
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• 2016

The epidermal growth factor receptor(EGFR) protein kinase signaling is an important pathway in cancer development and recently reported that EGFR and its kinase domain molecules are mutated in various of cancers including head and neck cancer. Functional deregulation of EGFR due to mutations in coding exons and copy number amplification is the most common event in cancers, especially among receptor tyrosine kinases(TK). We have analyzed Korean oral squamous cell carcinomas (OSCC) cell lines for mutations in EGFRTK. Exons encoding the hot-spot regions in the TK domain of EGFR (exons 17 to 23) were amplified by using polymerase chain reaction(PCR) and sequenced directly. EGFR expression was also analyzed in 8 OSCC cell lines using western blotting. Data analysis of the EGFR exons 17 to 23 coding sequences did not show any mutations in the 8 OSCC cell lines that were analyzed. The absence of mutations indicate that protein overexpression might be responsible for activation rather than mutation.

• Animal cells and systems
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• 제6권1호
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• pp.1-12
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• 2002

A role of Src family protein Tyrosine kinases (SFK) as mediators of receptor-ligand initiated responses is well established. Well documented, but less well understood is the role of SFK in cellular reaction to stresses. Evidence from the wide variety of experimental systems indicates that SFK mediate responses to all major classes of stress, including oxidation, DNA damage, mechanical impacts, and protein denaturing. SFK may be activated by stresses directly or via regulatory circuits whose identity is not yet fully understood. Depending on the cell type and the nature of activating stimulus, SFK may activate known downstream signaling cascades leading to cell survival, proliferation, cytoskeletal rearrangement, and apoptosis; the identity of these cascades is discussed. As in the case of receptor-initiated signaling, roles of individual SFK in various stress response may be redundant or non-redundant. Although signals generated by different stresses are generally transduced via distinct SFK pathways, these pathways may overlap or exhibit crosstalk. In some cell types stress-induced activation of SFK promotes survival and inhibits apoptosis, whereas the opposite may be true for other cell types. Stress responses constitute a new and rapidly developing area of SFK-mediated signaling.

• IMMUNE NETWORK
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• 제5권3호
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• pp.144-149
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• 2005

Background: Fc receptor-mediated phagocytosis is a complex process involving the activation of kinases and phosphatases. FcgammaRIIB has been known to transduces inhibitory signals through an immunoreceptor tyrosine-based inhibitory motif (ITIM) in cytoplasmic domains. In this study, we examined the involvement of inositol-phosphatase in the Fc receptor-mediated phagocytosis. Methods: J774 cells were infected using vaccinia viral vector containing SH2 domain-containing inositol-phosphatase (SHIP) cDNA and stimulated with the sensitized sheep red blood cells. Results: Stimulation of J774 cells induced the tyrosine phosphorylation of SHIP which was maximal at 5 minutes. Phosphatidylinositol-3 (PI-3) kinase inhibitor (wortmannin) inhibits J774 cell phagocytosis of sensitized sheep red blood cells in a dose-dependent manner. Heterologious expression of SHIP in J774 cells inhibits phagocytosis of sensitized sheep red blood cells in a dose-dependency manner, but catalytically dead mutants of SHIP has no effect on phagocytosis. Conclusion: These results strongly suggest that the active signals mediated by PI-3 kinase are opposed by inhibitory signals through SHIP in the regulation of Fc receptor-mediated phagocytosis.

• BMB Reports
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• 제41권12호
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• pp.833-839
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• 2008

Angiogenesis in tumors is driven by multiple growth factors that activate receptor tyrosine kinases. An important driving force of angiogenesis in solid tumors is signaling through vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Angiogenesis inhibitors that target this signaling pathway are now in widespread use for the treatment of cancer. However, when used alone, inhibitors of VEGF/VEGFR signaling do not destroy all blood vessels in tumors and do not slow the growth of most human cancers. VEGF/VEGFR signaling inhibitors are, therefore, used in combination with chemotherapeutic agents or radiation therapy. Additional targets for inhibiting angiogenesis would be useful for more efficacious treatment of cancer. One promising target is the signaling pathway of hepatocyte growth factor (HGF) and its receptor (HGFR, also known as c-Met), which plays important roles in angiogenesis and tumor growth. Inhibitors of this signaling pathway have been shown to inhibit angiogenesis in multiple in vitro and in vivo models. The HGF/c-Met signaling pathway is now recognized as a promising target in cancer by inhibiting angiogenesis, tumor growth, invasion, and metastasis.

• Genomics & Informatics
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• 제21권3호
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• pp.30.1-30.13
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• 2023

Ephs belong to the largest family of receptor tyrosine kinase and are highly conserved both sequentially and structurally. The structural organization of Eph is similar to other receptor tyrosine kinases; constituting the extracellular ligand binding domain, a fibronectin domain followed by intracellular juxtamembrane kinase, and SAM domain. Eph binds to respective ephrin ligand, through the ligand binding domain and forms a tetrameric complex to activate the kinase domain. Eph-ephrin regulates many downstream pathways that lead to physiological events such as cell migration, proliferation, and growth. Therefore, considering the importance of Eph-ephrin class of protein in tumorigenesis, 7,620 clinically reported missense mutations belonging to the class of variables of unknown significance were retrieved from cBioPortal and evaluated for pathogenicity. Thirty-two mutations predicted to be pathogenic using SIFT, Polyphen-2, PROVEAN, SNPs&GO, PMut, iSTABLE, and PremPS in-silico tools were found located either in critical functional regions or encompassing interactions at the binding interface of Eph-ephrin. However, seven were reported in nonsmall cell lung cancer (NSCLC). Considering the relevance of receptor tyrosine kinases and Eph in NSCLC, these seven mutations were assessed for change in the folding pattern using molecular dynamic simulation. Structural alterations, stability, flexibility, compactness, and solvent-exposed area was observed in EphA3 Trp790Cys, EphA7 Leu749Phe, EphB1 Gly685Cys, EphB4 Val748Ala, and Ephrin A2 Trp112Cys. Hence, it can be concluded that the evaluated mutations have potential to alter the folding pattern and thus can be further validated by in-vitro, structural and in-vivo studies for clinical management.