Parsing ERK Activation Reveals Quantitatively Equivalent Contributions From Epidermal Growth Factor Receptor and HER2 In Human Mammary Epithelial Cells

Journal Article · Fri Feb 18 04:00:00 EST 2005 · Journal of Biological Chemistry, 280(7):6157-6169

DOI:https://doi.org/10.1074/jbc.M410491200· OSTI ID:15020605

Hendriks, Bart S; Orr, Galya; Wells, Alan H; Wiley, H S; Lauffenburger, Douglas A

HER2, a member of the EGFR tyrosine kinase family, functions as an accessory EGFR signaling component and alters EGFR trafficking by heterodimerization. HER2 overexpression leads to aberrant cell behavior including enhanced proliferation and motility. Here we apply a combination of computational modeling and quantitative experimental studies of the dynamic interactions between EGFR and HER2, and their downstream activation of extracellular signal-related kinase (ERK) to understand this complex signaling system. Using cells expressing different levels of HER2 relative to the EGFR, we can separate relative contributions of EGFR and HER2 to signaling amplitude and duration. Based on our model calculations, we demonstrate that, in contrast with previous suggestions in the literature, the intrinsic capabilities of EGFR and HER2 to activated ERK are quantitatively equivalent . We find that HER2-mediated effects on EGFR dimerization and trafficking are sufficient to explain the detected HER2-mediated amplification of EGF-induced ERK signaling. Our model suggests that transient amplification of ERK activity by HER2 arises predominantly from the 2-to-1 stoichiometry of receptor kinase to bound ligand in EGFR/HER2 heterodimers compared to the 1-to-1 stoichiometry of the EGFR homodimer, but alterations in receptor trafficking, with resultant EGFR sparing, cause the sustained HER2-mediated enhancement of ERK signaling.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 15020605
• Report Number(s): PNNL-SA-43533; 25400; 6494
• Journal Information: Journal of Biological Chemistry, 280(7):6157-6169, Journal Name: Journal of Biological Chemistry, 280(7):6157-6169 Journal Issue: 7 Vol. 280
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL PROTECTION
AMPLIFICATION
AMPLITUDES
DIMERIZATION
Environmental Molecular Sciences Laboratory
GROWTH FACTORS
PARSING ERK ACTIVATION
EGFR
MAMMARY EPITHELIAL CELLS
PHOSPHOTRANSFERASES
PROLIFERATION
SIMULATION
STOICHIOMETRY
TRANSIENTS
TYROSINE