Grb2, a double-edged sword of receptor tyrosine kinase signaling

Abstract

Receptor tyrosine kinases (RTKs) exhibit basal tyrosine phosphorylation and activity in the absence of ligand stimulation, which has been attributed to the "leaky" nature of tyrosine kinase autoinhibition and stochastic collisions of receptors in the membrane bilayer. This basal phosphorylation does not produce a signal of sufficient amplitude and intensity to manifest in a biological response and hence is considered to be a passive, futile process that does not have any biological function. This paradigm has now been challenged by a study showing that the basal phosphorylation of RTKs is a physiologically relevant process that is actively inhibited by the intracellular adaptor protein growth factor receptor-bound 2 (Grb2) and serves to "prime" receptors for a rapid response to ligand stimulation. Grb2 is conventionally known for playing positive roles in RTK signaling. The discovery of a negative regulatory role for Grb2 reveals that this adaptor acts as a double-edged sword in the regulation of RTK signaling.

Fig. 1

Models of basal receptor phosphorylation and ligand-mediated activation. (A) Diffusion-based model. Receptors float laterally within the plasma membrane, making occasional collisions that result in basal phosphorylation and activation of the receptor. This stochastic process is limited by the diffusion rate constant of the receptor. (B) Preformed dimer model. Receptor ectodomains interact homotypically, resulting in preformed dimers. However, the orientation of these dimers is not conducive to transphosphorylation of kinase domains. Diffusion is not a rate-limiting factor. (C) Intracellular Grb2-mediated receptor dimerization model. Receptors are held in close proximity by a Grb2 dimer. The C-terminal SH3 domains of Grb2 bind the C-terminal tail P-X-X-P motif of the receptor. The close proximity of the kinase domains allows for increased basal phosphorylation on the A-loop, but downstream signaling is not permitted because of steric hindrances imposed by Grb2 on phosphoryation of recruitment-site tyrosines. (D) Ligand-induced receptor activation. Ligand binding enables the receptor to adopt the proper orientation required for effective receptor transphosphorylation of tyrosine residues. This transphorylation links the receptor to activation of specific downstream pathways, eliciting a robust signaling response and unique cellular outcomes. Distinct pools of Grb2 relay the signal from the activated receptors to different proteins and secondary messengers.