Related Experiment Video

Updated: May 27, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Mechanistic insights into the activation of oncogenic forms of EGF receptor

Zhihong Wang1, Patti A Longo, Mary Katherine Tarrant

  • 1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Nature Structural & Molecular Biology
|November 22, 2011
PubMed

Insights

Two oncogenic mutants of the epidermal growth factor receptor (EGFR) are highly active and resistant to inhibitors. These mutants depend on asymmetric kinase dimer formation for activation, impacting cancer drug design.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Epidermal growth factor receptor (EGFR) mutations drive non-small cell lung cancer.
  • Oncogenic EGFR activation mechanisms, particularly dimer independence, remain unclear.
  • Previous studies relied on cell-based assays or isolated kinase domains.

Purpose of the Study:

  • Investigate the activation mechanism of oncogenic EGFR mutants.
  • Determine the role of kinase dimerization in mutant EGFR activity.
  • Assess the efficacy of inhibitors against oncogenic EGFR mutants.

Main Methods:

  • Purified, near full-length human EGFR proteins (tEGFRs) were utilized.
  • Assays were performed to measure activity independently of EGF.
  • Inhibition patterns with therapeutic and endogenous inhibitors were analyzed.
  • Asymmetric kinase dimer interface mutations were introduced and studied.

Main Results:

  • Two oncogenic EGFR mutants demonstrated high activity independent of EGF.
  • These mutants exhibited significant resistance to cetuximab, lapatinib, and MIG6.
  • Analysis suggested oncogenic mutants drive and depend on asymmetric kinase dimer formation for activation.

Conclusions:

  • Oncogenic EGFR mutants activate through a mechanism dependent on asymmetric kinase dimers.
  • This activation pathway is distinct from wild-type EGFR and confers inhibitor resistance.
  • Findings have implications for developing targeted therapies and improving cancer treatment strategies.

More Related Videos

Studying the Stoichiometry of Epidermal Growth Factor Receptor in Intact Cells using Correlative Microscopy09:16

Studying the Stoichiometry of Epidermal Growth Factor Receptor in Intact Cells using Correlative Microscopy

Published on: September 11, 2015

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
Activation of Integrins01:15

Activation of Integrins

Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...