scholarly journals Involvement of N-glycan in Multiple Receptor Tyrosine Kinases Targeted by Ling-Zhi-8 for Suppressing HCC413 Tumor Progression

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 9 ◽  
Author(s):  
Ren-In You ◽  
Wen-Sheng Wu ◽  
Chuan-Chu Cheng ◽  
Jia-Ru Wu ◽  
Siou-Mei Pan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tyrosine Kinases ◽  
Poor Prognosis ◽  
Tumor Metastasis ◽  
Receptor Tyrosine Kinases ◽  
Target Therapy ◽  
Downstream Signaling ◽  
The Poor ◽  
And Function ◽  
Multiple Receptor

The poor prognosis of hepatocellular carcinoma (HCC) is resulted from tumor metastasis. Signaling pathways triggered by deregulated receptor tyrosine kinases (RTKs) were the promising therapeutic targets for prevention of HCC progression. However, RTK-based target therapy using conventional kinase-based inhibitors was often hampered by resistances due to compensatory RTKs signaling. Herein, we report that Ling-Zhi-8 (LZ-8), a medicinal peptide from Ganoderma lucidium, was effective in suppressing cell migration of HCC413, by decreasing the amount and activity of various RTKs. These led to the suppression of downstream signaling including phosphorylated JNK, ERK involved in HCC progression. The capability of LZ-8 in targeting multiple RTKs was ascribed to its simultaneous binding to these RTKs. LZ-8 may bind on the N-linked glycan motif of RTKs that is required for their maturation and function. Notably, pretreatment of the N-glycan trimming enzyme PNGase or inhibitors of the mannosidase (N-glycosylation processing enzyme), kifunensine (KIF) and swainsonine (SWN), prevented LZ-8 binding on the aforementioned RTKs and rescued the downstream signaling and cell migration suppressed by LZ-8. Moreover, pretreatment of KIF prevented LZ-8 triggered suppression of tumor growth of HCC413. Our study suggested that a specific type of N-glycan is the potential target for LZ-8 to bind on multiple RTKs for suppressing HCC progression.

scholarly journals Receptor Tyrosine Kinases in Kidney Development

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Renfang Song ◽  
Samir S. El-Dahr ◽  
Ihor V. Yosypiv
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Receptor Tyrosine Kinases ◽  
Adaptor Proteins ◽  
Downstream Signaling ◽  
Arterial Blood ◽  
Intracellular Signal ◽  
Human Birth

The kidney plays a fundamental role in the regulation of arterial blood pressure and fluid/electrolyte homeostasis. As congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common human birth defects, improved understanding of the cellular and molecular mechanisms that lead to CAKUT is critical. Accumulating evidence indicates that aberrant signaling via receptor tyrosine kinases (RTKs) is causally linked to CAKUT. Upon activation by their ligands, RTKs dimerize, undergo autophosphorylation on specific tyrosine residues, and interact with adaptor proteins to activate intracellular signal transduction pathways that regulate diverse cell behaviours such as cell proliferation, survival, and movement. Here, we review the current understanding of role of RTKs and their downstream signaling pathways in the pathogenesis of CAKUT.

scholarly journals Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Sareshma Sudhesh Dev ◽  
Syafiq Asnawi Zainal Abidin ◽  
Reyhaneh Farghadani ◽  
Iekhsan Othman ◽  
Rakesh Naidu
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Surface Proteins ◽  
Downstream Signaling ◽  
Anti Cancer ◽  
Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

CIP4 Targeted to Recruit GTP-Cdc42 Involving in Invadopodia Formation Through NF-κB Signaling Pathway Promotes Invasion and Metastasis of Colorectal Cancer

2021 ◽  
Author(s):  
Zhiyan Hu ◽  
Jiaxian Zhu ◽  
Yidan Ma ◽  
Ting Long ◽  
Lingfang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Tumor Metastasis ◽  
Migration And Invasion ◽  
Downstream Signaling ◽  
And Function ◽  
Downstream Signaling Pathway ◽  
Invadopodia Formation

Abstract Background CIP4 (Cdc42-interacting protein 4), a member of the F-BAR family which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and closely associated with tumor invadopodia formation. However, the specific mechanism of the interaction between CIP4 and Cdc42 as well as the downstream signaling pathway in response in colorectal cancer (CRC) remains unknown, which is worth exploring for its impact on tumor infiltration and metastasis. Methods Immunohistochemistry and western blot analyses were performed to detect the expression of CIP4 and Cdc42. Their relationship with CRC clinicopathological characteristics was further analyzed. Wound-healing, transwell migration and invasion assays tested the effect of CIP4 on cells migration and invasion ability in vitro, and the orthotopic xenograft colorectal cancer mouse mode evaluated the tumor metastasis in vivo. The invadopodia formation and function were assessed by immunofluorescence, scanning electron microscopy (SEM) and matrix degradation assay. The interaction between CIP4 and Cdc42 was confirmed by co-immunoprecipitation (co-IP) and GST-Pull down assays. Immunofluorescence was used to observed the colocalization of CIP4, GTP-Cdc42 and invadopodia. The related downstream signaling pathway was investigated by western blot and immunofluorescence. Results CIP4 expression was significantly higher in human colorectal cancer tissues and correlated with the CRC infiltrating depth and metastasis as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability in vitro and the tumor metastasis in vivo, while overexpression of CIP4 confirmed the opposite situation by promoting invadopodia formation and matrix degradation ability. In addition, we identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4 to participate in this process. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression CRC cells contributing to invadopodia formation while inhibition of either CIP4 or Cdc42 led to suppression of NF-κB pathway resulted in decrease quantity of invadopodia. Conclusion Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis.

scholarly journals SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1558 ◽  
Author(s):  
Claudia Cirotti ◽  
Claudia Contadini ◽  
Daniela Barilà
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Metabolic Reprogramming ◽  
Constitutive Activity ◽  
Therapeutic Approaches ◽  
Resistance To Therapy ◽  
Downstream Signaling ◽  
Wide Range ◽  
Therapy Effectiveness

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

scholarly journals Tyrosine Kinase BMX Phosphorylates Phosphotyrosine-Primed Motif Mediating the Activation of Multiple Receptor Tyrosine Kinases

2013 ◽  
Vol 6 (277) ◽  
pp. ra40-ra40 ◽  
Author(s):  
S. Chen ◽  
X. Jiang ◽  
C. A. Gewinner ◽  
J. M. Asara ◽  
N. I. Simon ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Multiple Receptor

Profiling of activated receptor tyrosine kinases in advanced gastric cancers identifies patients with poor prognosis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4011-4011
Author(s):  
Phillip Sangwook Kim ◽  
Jeeyun Lee ◽  
Sung Kim ◽  
Xinjun Liu ◽  
Joon Oh Park ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Poor Prognosis ◽  
Receptor Tyrosine Kinases ◽  
Resistance Mechanism ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Small Subset ◽  
Trastuzumab Resistance ◽  
Free Survival

4011 Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge due to its poor prognosis. Trastuzumab is the only known targeted therapy that has demonstrated a survival benefit in a small subset of metastatic GCAs. Addition of molecular diagnostics for predicting prognosis and therapeutic outcomes can significantly enhance the clinical management of GCAs. Herein, we identify activated receptor tyrosine kinases (RTKs) in distinct GCA subsets that correlate with disease-free survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Results: p95HER2, a known trastuzumab resistance mechanism, was identified for the first time in 79% of IHC/FISH-based HER2(+) GCAs. Full-length HER2 expression was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 protein. 232/434 GCAs expressed at least one activated RTK analyzed in our study. Of these 232 patients, 121 patients that presented with stage II or III disease at the time of surgery; demonstrated a worse progression-free survival as compared to those where none of the analyzed RTKs were activated (32.6 months vs 76.5 months, p=0.0318). HER axis members were the most commonly activated RTKs with 64% of such GCAs. Approximately 71% of activated cMET tumors demonstrated a co-activation with a HER axis member with a preference for HER1 in ~61% of cMET-activated GCAs. Patients with p-MET(+):p-HER1(+) GCAs had a worse prognosis as compared to those with p-MET(+):p-HER1(-) GCAs (46.2 months vs 82.8 months, p=0.0184). Conclusions: CEER-based RTK characterization revealed concomitantly activated signaling pathways in GCAs which could predict disease recurrence. Comprehensive molecular profiles of GCA tumors can allow for the implementation of these companion biomarkers in GCA therapeutic clinical trials.

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