Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity

Abstract

Abbreviations used in this paper: C-SH3, C-terminal SH3 domain; ERK, extracellular signal-regulated kinase; FGFR2, fibroblast growth factor receptor 2; FLIM, fluorescence lifetime imaging microscopy; FRET, fluorescence resonance energy transfer; FRS2, FGFR substrate 2; Grb2, growth factor receptor-bound protein 2; MAP, mitogen-activated protein; RTK, receptor tyrosine kinase; Shp2, SH2 domaincontaining protein tyrosine phosphatase 2.

Functions of Shp2 in cancer

“…Likewise, Shp2 can be phosphorylated by stimulation with growth factors or cytokines, such as EGF , and hepatocyte growth factor , to activate the Ras‐Erk signalling pathway. Glycoprotein gp130 (CD130) and GFR interact with Shp2 to mediated signalling; as such, the mechanism by which Shp2 is phosphorylated by various exogenous stimuli has been widely studied. Furthermore, one (or both) of these tyrosines should be phosphorylated to activate Shp2.…”

“…Grb2 controls fibroblast GFR 2 (FGFR2) phosphorylation by inhibiting receptor kinase and Shp2 phosphatase activity . Thus, Shp2 is a critical mediator of the activation of the PI3K‐Akt signalling pathway .…”

“…Grb2 should be considered in studies in involving Shp2, because the interaction between Grb2 and Shp2 is essential to activate the downstream pathway of Erk . Activated Shp2 recruits Grb2; phosphorylated Tyr580 of Shp2 functions as the main binding site of Grb2, thereby activating Ras in response to growth factor .…”

Fluorescence lifetime imaging (FLIM): Basic concepts and some recent developments

“…4, where cyan fluorescent protein (CFP)-labelled growth factor receptor-bound protein 2 (CFP-Grb2) interacts with RFP-tagged wild-type SH2 domain-containing protein tyrosine phosphatase 2 (RFP-WT Shp2) after stimulation with 20 ng/ml fibroblast growth factor 9 (FGF9). After 15 min stimulation with FGF9, protein interaction is induced as indicated by the reduced average fluorescence lifetime of the CFP donor (Ahmed et al, 2013). In addition, FRET is also frequently used to study conformational changes within a protein (Hunt et al, 2012), or cleavage of a protein (Harpur et al, 2001) or as a sensor, e.g.…”

“…have a shorter lifetime). The photobleaching is usually associated with the triplet state, and the probability of populating it is reduced when the fluorescence Figure 4 An example of FRET between CFP-donor-labelled proteins, and RFP-acceptor-labelled proteins, from (Ahmed et al, 2013). Interaction of CFP-labelled growth factor receptor-bound protein 2 (CFP-Grb2) with RFP-tagged wild-type SH2 domaincontaining protein tyrosine phosphatase 2 (RFP-WT Shp2) at basal and after stimulation with 20 ng/ml fibroblast growth factor 9 (FGF9).…”