EGF receptor function is required in late G1 for cell cycle progression induced by bombesin and bradykinin

2001 ◽  
Vol 281 (3) ◽  
pp. C886-C898 ◽  
Author(s):  
Chintda Santiskulvong ◽  
James Sinnett-Smith ◽  
Enrique Rozengurt
Keyword(s):  
Cell Cycle ◽  
Tyrosine Kinase ◽  
Dna Synthesis ◽  
Kinase Inhibitors ◽  
Egf Receptor ◽  
3T3 Cells ◽  
Erk Activation ◽  
Egfr Tyrosine Kinase ◽  
Swiss 3T3

We examined the role of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase activation in G protein-coupled receptor (GPCR) agonist-induced mitogenesis in Swiss 3T3 and Rat-1 cells. Addition of EGFR tyrosine kinase inhibitors (e.g., tyrphostin AG-1478) abrogated bombesin-induced extracellular signal-regulated kinase (ERK) activation in Rat-1 cells but not in Swiss 3T3 cells, indicating the importance of cell context in determining the role of EGFR in ERK activation. In striking contrast, treatment with tyrphostin AG-1478 markedly (∼70%) inhibited DNA synthesis induced by bombesin in both Swiss 3T3 and Rat-1 cells. Similar inhibition of bombesin-induced DNA synthesis in Swiss 3T3 cells was obtained using four structurally different inhibitors of EGFR tyrosine kinase. Furthermore, kinetic analysis indicates that EGFR function is necessary for bombesin-induced mitogenesis in mid-late G1 in both Swiss 3T3 and Rat-1 cells. Our results indicate that EGFR kinase activity is necessary in mid-late G1 for promoting the accumulation of cyclins D1 and E and implicate EGFR function in the coupling of GPCR signaling to the activation of the cell cycle.

Role of Ras in metal-induced EGF receptor signaling and NF-κB activation in human airway epithelial cells

2002 ◽  
Vol 282 (5) ◽  
pp. L1040-L1048 ◽  
Author(s):  
Weidong Wu ◽  
Ilona Jaspers ◽  
Wenli Zhang ◽  
Lee M. Graves ◽  
James M. Samet
Keyword(s):  
Tyrosine Kinase ◽  
Egf Receptor ◽  
Ambient Air ◽  
Serine Phosphorylation ◽  
Mutant Form ◽  
Airway Epithelial ◽  
Egfr Signaling ◽  
Human Airway ◽  
Egfr Tyrosine Kinase

We showed previously that epithelial growth factor (EGF) receptor (EGFR) signaling is triggered by metallic compounds associated with ambient air particles. Specifically, we demonstrated that As, Zn, and V activated the EGFR tyrosine kinase and the downstream kinases MEK1/2 and ERK1/2. In this study, we examined the role of Ras in EGFR signaling and the nuclear factor-κB (NF-κB) activation pathway and the possible interaction between these two signaling pathways in a human airway epithelial cell line (BEAS-2B) exposed to As, V, or Zn ions. Each metal significantly increased Ras activity, and this effect was inhibited by the EGFR tyrosine kinase activity inhibitor PD-153035. Adenoviral-mediated overexpression of a dominant-negative mutant form of Ras(N17) significantly blocked MEK1/2 or ERK1/2 phosphorylation in As-, Zn-, or V-exposed BEAS-2B cells but caused little inhibition of V-, Zn- or EGF-induced EGFR tyrosine phosphorylation. This confirmed Ras as an important intermediate effector in EGFR signaling. Interestingly, V, but not As, Zn, or EGF, induced IκBα serine phosphorylation, IκBα breakdown, and NF-κB DNA binding. Moreover, PD-153035 and overexpression of Ras(N17) each significantly blocked V-induced IκBα breakdown and NF-κB activation, while inhibition of MEK activity with PD-98059 failed to do so. In summary, exposure to As, Zn, and V initiated EGFR signaling and Ras-dependent activation of MEK1/2 and ERK1/2, but only V induced Ras-dependent NF-κB nuclear translocation. EGFR signaling appears to cross talk with NF-κB signaling at the level of Ras, but additional signals appear necessary for NF-κB activation. Together, these data suggest that, in V-treated BEAS-2B cells, Ras-dependent signaling is essential, but not sufficient, for activation of NF-κB.

scholarly journals Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors

Oncogene ◽  
2003 ◽  
Vol 22 (18) ◽  
pp. 2812-2822 ◽  
Author(s):  
Roberto Bianco ◽  
Incheol Shin ◽  
Christoph A Ritter ◽  
F Michael Yakes ◽  
Andrea Basso ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egf Receptor ◽  
Antitumor Action ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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