Ras/MAPK Activation by SHP2. (A) SHP2 modulates Ras signaling activation downstream of RTKs by functioning as a scaffold for SOS-mediated guanine nucleotide exchange and as an enzyme that dephosphorylates multiple substrates, including known negative regulators of Ras-GTP. (B) In the inactive conformation, SHP2 PTPase activity is autoinhibited by the N-SH2 domain. (C) Upon recruitment by activated RTKs, the SHP2 adopts an open (active) state, exposing the catalytic site and the scaffold docking sites. (D) Allosteric SHP2 inhibitors stabilize the closed conformation, hampering both the catalytic and the scaffold functions.