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.

Figure 1

Domain organization of RTKs. The following abbreviations are used: L, leucine-rich; CR, cysteine-rich; Ig, immunoglobulin-like; FnIII, fibronectin type III; ID, insert domain. The L1, CR1, L2 and CR2 domains of the ErbB family are alternatively termed Domains I–IV. The ErbB and Trk families are drawn as a monomer, but might be present as non-covalently formed dimers at the cell surface prior to ligand binding (see the main text). Not drawn to scale.

Figure 2

Schematic representations of the structures of the extracellular regions of the ErbB family. EGFR, ErbB3 and ErbB4 adopt the tethered conformation in the absence of ligand, while ErbB2 adopts an extended, or untethered, conformation that resembles the ligand-activated, dimerization-competent EGFR protomer in the ligand-bound form of the EGFR dimer, shown at the right. The ‘dimerization arm’ and ‘tethering arm’ are shown by an asterisk and an open triangle, respectively. Ligands are shown in red. Domains I–IV correspond to the domains shown in Figure 1. Not drawn to scale.

Figure 3

Models for ligand-induced activation of the ErbB family. (A) ‘Dimerization’ model. (B) ‘Rotation/twist’ model. For the explanation of the models, see the main text. Not drawn to scale.