Specificity protein 1 regulates fascin expression in esophageal squamous cell carcinoma as the result of the epidermal growth factor/extracellular signal-regulated kinase signaling pathway activation

2010 ◽  
Vol 67 (19) ◽  
pp. 3313-3329 ◽  
Author(s):  
Xiao-Feng Lu ◽  
En-Min Li ◽  
Ze-Peng Du ◽  
Jian-Jun Xie ◽  
Zhang-Yan Guo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Growth Factor ◽  
Esophageal Squamous Cell Carcinoma ◽  
Extracellular Signal Regulated Kinase ◽  
Specificity Protein 1 ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
Epidermal Growth ◽  
Specificity Protein ◽  
Kinase Signaling Pathway

scholarly journals Larotinib in patients with advanced and previously treated esophageal squamous cell carcinoma with epidermal growth factor receptor overexpression or amplification: an open-label, multicenter phase 1b study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rongrui Liu ◽  
Lianke Liu ◽  
Chuanhua Zhao ◽  
Yuxian Bai ◽  
Yulong Zheng ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Growth Factor Receptor ◽  
Open Label ◽  
Phase 1B ◽  
Epidermal Growth

Abstract Background Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. Methods Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). Results 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9–10.2) months and 3.4 (95% CI 2.4–3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. Conclusions Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. Trial registration This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092.

scholarly journals Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

2013 ◽  
Vol 33 (22) ◽  
pp. 4538-4551 ◽  
Author(s):  
Junfeng Tong ◽  
Laiji Li ◽  
Barbara Ballermann ◽  
Zhixiang Wang
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Rho Gtpases ◽  
Fluorescent Protein ◽  
Phosphorylation Site ◽  
Kinase Assay ◽  
Nucleotide Exchange ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Epidermal Growth

Accumulating evidence has implicated Rho GTPases, including Rac1, in many aspects of cancer development. Recent findings suggest that phosphorylation might further contribute to the tight regulation of Rho GTPases. Interestingly, sequence analysis of Rac1 shows that Rac1 T108 within the106PNTP109motif is likely an extracellular signal-regulated kinase (ERK) phosphorylation site and that Rac1 also has an ERK docking site,183KKRKRKCLLL192(D site), at the C terminus. Indeed, we show here that both transfected and endogenous Rac1 interacts with ERK and that this interaction is mediated by its D site. Green fluorescent protein (GFP)-Rac1 is threonine (T) phosphorylated in response to epidermal growth factor (EGF), and EGF-induced Rac1 threonine phosphorylation is dependent on the activation of ERK. Moreover, mutant Rac1 with the mutation of T108 to alanine (A) is not threonine phosphorylated in response to EGF.In vitroERK kinase assay further shows that pure active ERK phosphorylates purified Rac1 but not mutant Rac1 T108A. We also show that Rac1 T108 phosphorylation decreases Rac1 activity, partially due to inhibiting its interaction with phospholipase C-γ1 (PLC-γ1). T108 phosphorylation targets Rac1 to the nucleus, which isolates Rac1 from other guanine nucleotide exchange factors (GEFs) and hinders Rac1's role in cell migration. We conclude that Rac1 T108 is phosphorylated by ERK in response to EGF, which plays an important role in regulating Rac1.

Regulation of MEK/ERK pathway output by subcellular localization of B-Raf

2012 ◽  
Vol 40 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Catherine Andreadi ◽  
Catherine Noble ◽  
Bipin Patel ◽  
Hong Jin ◽  
Maria M. Aguilar Hernandez ◽  
...  
Keyword(s):  
Growth Factor ◽  
Subcellular Localization ◽  
Signalling Pathway ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Intracellular Signalling Pathway ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
A Cell ◽  
Phase Entry

The strength and duration of intracellular signalling pathway activation is a key determinant of the biological outcome of cells in response to extracellular cues. This has been particularly elucidated for the Ras/Raf/MEK [mitogen-activated growth factor/ERK (extracellular-signal-regulated kinase) kinase]/ERK signalling pathway with a number of studies in fibroblasts showing that sustained ERK signalling is a requirement for S-phase entry, whereas transient ERK signalling does not have this capability. A major unanswered question, however, is how a cell can sustain ERK activation, particularly when ERK-specific phosphatases are transcriptionally up-regulated by the pathway itself. A major point of ERK regulation is at the level of Raf, and, to sustain ERK activation in the presence of ERK phosphatases, sustained Raf activation is a requirement. Three Raf proteins exist in mammals, and the activity of all three is induced following growth factor stimulation of cells, but only B-Raf activity is maintained at later time points. This observation points to B-Raf as a regulator of sustained ERK activation. In the present review, we consider evidence for a link between B-Raf and sustained ERK activation, focusing on a potential role for the subcellular localization of B-Raf in this key physiological event.

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