ERBB receptors in cancer: signaling from the inside

The ERBB receptor family encompasses four transmembrane tyrosine kinases that regulate cell differentiation, mitogenesis, survival, and migration. Dysregulated function of these receptor tyrosine kinases has been shown to result in cell transformation and cancer [1]. This receptor family includes the epidermal growth factor receptor (EGFR/ERBB1), HER2/ERBB2, HER3/ERBB3, and HER4/ERBB4. Signaling is triggered by ligand binding to the extracellular domain of EGFR, ERBB3, and ERBB4, resulting in a conformational change in the receptor ectodomains and the dimerization of their cytoplasmic tyrosine kinase domains [2]. The receptor-receptor association releases the kinase domain from a default autoinhibited state, leading to transphosphorylation of tyrosine residues in the receptor C-terminus [3]. In turn, these phosphorylated tyrosines become docking sites for the specific binding of cytoplasmic signaling proteins containing Src homology-2 and protein tyrosine-binding domains, which then trigger several intracellular signaling pathways associated with cell growth and transformation [4].Dimerization and activation of the tyrosine kinase domain of ERBB receptors are highly regulated processes modulated by incompletely understood stimulatory and inhibitory inputs. Recent data suggest that the mere dimerization of EGFR is not sufficient for their activation [5]. Further, only a fraction of dimerized receptors appears catalytically active, particularly those receptors where the kinase domains are arranged as asymmetric dimers [6,7]. These data coupled with the observation that receptor dimers may occur in the absence of ligand [5] led to speculation on the presence of cytoplasmic activators that modulate the conversion of these receptor dimers into an active state.The study by Bill and colleagues now reports that cytohesins - guanine-nucleotide exchange factors of the ATP ribosylation factors involved in vesicular trafficking, cell migration, and cytoskeletal dynamics - facil