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

Abstract

Signaling 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.

Figure 1

Organization of a prototypical ErbB family receptor. Shown is a stylized depiction of the functional motifs. The extracellular domain is at the amino terminus and the cytoplasmic domain is at the carboxyl terminus. Examples of activating mutations in EGFR are listed.

Figure 2

Structure of the unliganded and liganded EGFR extracellular domain. Diagram showing the structure of the A unliganded EGFR extracellular domain, B EGFR extracellular domain in complex with EGF, and C dimerized liganded EGFR extracellular domains. Adapted from Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA et al. 2005 Mol Cell Biol 25:7734–7742.

Figure 3

Structure of the EGFR tyrosine kinase domain. Shown is a stylized depiction of the structure of the A monomeric tyrosine kinase domain and of the B dimeric kinase domain. Adapted from Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. 2006 Cell 125: 1137–1149.