Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers

Abstract

Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights.

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“…However, numerous studies have demonstrated that prior to ligand binding, EGFR exists in dimeric, yet inactive, form at the cell surface [8,36]. By using different chemical cross-linkers from those previously employed, it is found that EGFR exists in dimeric form prior to ligand binding [37,38].…”

“…The receptor is activated by binding of various ligands including epidermal growth factor (EGF), transforming growth factor α (TGFα), amphiregulin (AREG), epigen, β-cellulin, heparin-binding EGF (HB-EGF) and epiregulin [6,7]. EGFR is a singlepass transmembrane protein, consisting of an extracellular domain, a transmembrane domain, a juxtamembrane (JM) segment, a kinase domain, and a C-terminal regulatory tail ( Figure 1) [8,9]. Upon ligand binding, the C-terminal tail becomes tyrosinephosphorylated, and mediates interactions between the receptor and downstream effectors such as Shc1 and Grb2 [10].…”