scholarly journals Label-free cell phenotypic assessment of the molecular mechanism of action of epidermal growth factor receptor inhibitors

RSC Advances ◽  
2013 ◽  
Vol 3 (26) ◽  
pp. 10370 ◽  
Author(s):  
Huayun Deng ◽  
Chaoming Wang ◽  
Ye Fang
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Growth Factor Receptor ◽  
Free Cell ◽  
Label Free ◽  
Molecular Mechanism Of Action ◽  
Epidermal Growth

scholarly journals Molecular Mechanism for a Role of SHP2 in Epidermal Growth Factor Receptor Signaling

2003 ◽  
Vol 23 (21) ◽  
pp. 7875-7886 ◽  
Author(s):  
Yehenew M. Agazie ◽  
Michael J. Hayman
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Molecular Mechanism ◽  
Receptor Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Signaling ◽  
Epidermal Growth

ABSTRACT The Src homology 2-containing phosphotyrosine phosphatase (SHP2) is primarily a positive effector of receptor tyrosine kinase signaling. However, the molecular mechanism by which SHP2 effects its biological function is unknown. In this report, we provide evidence that defines the molecular mechanism and site of action of SHP2 in the epidermal growth factor-induced mitogenic pathway. We demonstrate that SHP2 acts upstream of Ras and functions by increasing the half-life of activated Ras (GTP-Ras) in the cell by interfering with the process of Ras inactivation catalyzed by Ras GTPase-activating protein (RasGAP). It does so by inhibition of tyrosine phosphorylation-dependent translocation of RasGAP to the plasma membrane, to its substrate (GTP-Ras) microdomain. Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, which may also serve as a model to describe its role in other receptor tyrosine kinase signaling pathways.

scholarly journals A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yongjian Huang ◽  
Jana Ognjenovic ◽  
Deepti Karandur ◽  
Kate Miller ◽  
Alan Merk ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Molecular Mechanism ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Transforming Growth Factor Α ◽  
Epidermal Growth ◽  
Mechanistic Basis

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family.

Label-free imaging of epidermal growth factor receptor-induced response in single living cells

The Analyst ◽  
2018 ◽  
Vol 143 (21) ◽  
pp. 5264-5270 ◽  
Author(s):  
Zanying Peng ◽  
Jin Lu ◽  
Ling Zhang ◽  
Yang Liu ◽  
Jinghong Li
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Induced Response ◽  
Label Free ◽  
Epidermal Growth ◽  
Cell Signal Transduction ◽  
Single Living Cells ◽  
Single Living

Epidermal growth factor receptor (EGFR), which belongs to the second-largest protein family for cell signal transduction, plays crucial roles in homeostasis, cellular organized patterns and most human cancers.

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