GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of PI3K, GAB2 (GAB1 in Hayashi et al. 2000), and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000).
PTPN11 is recruited to RET via a combination of direct interactions and indirect interactions with other components of the receptor complex such as FRS2A and GAB1/2 (Perrinjaquet et al. 2010, Willecke et al. 2011). Binding of PTPN11 SH2-domains induces a conversion of the closed inactive into an open active structure (Willecke et al. 2011).
GAB2 interacts with the SH2 domains of PTPN11 (Gu et al. 1998, Crouin et al. 2001, Arnaud et al. 2004), which binds GAB2 Tyrosine (Y) 614 and Y643 through its N- and C-terminal SH2 domains respectively. Mutation of Y614 is sufficient to prevent GAB2 from recruiting PTPN11. In the Interleukin-2 receptor system, this prevents ERK (extracellular-signal-regulated kinase) activation (Arnaud et al. 2004). Similarly, phosphorylated GAB1 binds PTPN11, PI3K, PLCgamma1 and SHC1 in activated B cells (Ingham et al. 1998). GAB1 Y627 and Y659 appear to link it to PTPN11; GAB1 mutants that are unable to bind PTPN11 do not activate ERK (Schaeper et al. 2000, Cunnick et al. 2000, Sármay et al. 2006).