Mutational activation of ErbB family receptor tyrosine kinases: insights into mechanisms of signal transduction and tumorigenesis

Abstract

SummarySignaling by the Epidermal Growth Factor Receptor (EGFR) and related ErbB family receptor tyrosine kinases can be deregulated in human malignancies as the result of mutations in the genes that encode these receptors. The recent identification of EGFR mutations that correlate with sensitivity and resistance to EGFR tyrosine kinase inhibitors in lung and colon tumors has renewed interest in such activating mutations. Here we review current models for ligand stimulation of receptor dimerization and for activation of receptor signaling by receptor dimerization. In the context of these models, we discuss ErbB receptor mutations that affect ligand binding and those that cause constitutive receptor phosphorylation and signaling as a result of constitutive receptor dimerization. We discuss mutations in the cytoplasmic regions that affect enzymatic activity, substrate specificity and coupling to effectors and downstream signaling pathways. Finally, we discuss how emergent mechanisms of ErbB receptor mutational activation could impact the search for clinically relevant ErbB receptor mutations.

The Role of ErbB Receptors in Endometrial Cancer

“…The closed conformation (inactive), has intramolecular interactions between subdomains II and IV Dawson et al, 2005;Riese et al, 2007]. 2.…”

“…2. The open conformation (active), where subdomains I and III form a ligand-binding pocket that permits interactions between a single ligand and subdomains I and III Dawson et al, 2005;Riese et al, 2007]. In the absence of ligand binding, the extracellular region of EGFR, ErbB-3 and ErbB-4 has equilibrium between closed and open conformation Dawson et al, 2005;Ozcan et al, 2006;Riese et al, 2007].…”

“…In the absence of ligand binding, the extracellular region of EGFR, ErbB-3 and ErbB-4 has equilibrium between closed and open conformation Dawson et al, 2005;Ozcan et al, 2006;Riese et al, 2007]. This equilibrium favours the closed conformation [Ozcan et al, 2006;Riese et al, 2007]. Ligand binding stabilizes extracellular region in the open conformation and leads to the formation of both homodimeric and heterodimeric ErbB receptor complexes [Olayioye et al, 2000;Dawson et al, 2005;Ozcan et al, 2006;Riese et al, 2007].…”

A Brain-specific Grb2-associated Regulator of Extracellular Signal-regulated Kinase (Erk)/Mitogen-activated Protein Kinase (MAPK) (GAREM) Subtype, GAREM2, Contributes to Neurite Outgrowth of Neuroblastoma Cells by Regulating Erk Signaling

“…The EGF receptor is linked to the generation and development of human cancer, and EGF antagonists have been used to develop effective cancer therapeutics (2,3). The interactions between receptor tyrosine kinases and adaptor proteins are crucial for the transduction of intracellular growth signals from the plasma membrane to the nucleus (4,5).…”

Epidermal growth factor receptor revisited: Prognostic marker or target for therapy?

“…14 While such mutations have been identified in 10-30% of non-small cell lung cancer, 19 this is a less frequently documented event in colorectal cancer. 20 The investigators found only two patients with EGFR mutations in the kinase region in their patient population.…”