Fig. 1. SHP2-associated Noonan syndrome in RASopathy.

(Top) Domain structure of SHP2 and its activation by disease-associated mutations. SHP2 contains nSH2 and cSH2 domains in the N-terminal region, and a phosphatase [protein tyrosine phosphatase (PTP)] and an unstructured tail in the C-terminal region. The C-terminal tail contains two tyrosine phosphorylation sites (Tyr⁵⁴² and Tyr⁵⁸⁰) and a proline-rich domain with the PxxP motif. Upon upstream stimulation, the phosphorylated tyrosine (pY) motif of receptor tyrosine kinase (RTK) targets the SH2 domains of SHP2, recruiting it to the plasma membrane and releasing the autoinhibition of SHP2. Adapter proteins, such as Grb2-associated binding protein 1 (GAB1), also provide the pY motif, leading to recruitment of SHP2. Inactive SHP2 exhibits low basal activity owing to the autoinhibitory interaction between the nSH2 and PTP domains. Mutations in SHP2 causing human diseases, such as cancers or neurodevelopmental disorders, lead to gain of function. (Middle) These mutations mainly cluster in the nSH2-PTP interface, abolishing the inhibitory interaction. The locations and types of the germline mutations related to the NS and LEOPARD (LPRD) syndrome (also known as NS with multiple lentigines) are not the same as those responsible for the cancers, juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML), although the same residues are mutated. (Bottom left) Inactive SHP2 does not contribute to the MAPK pathway. (Bottom right) Active SHP2 mutants with open conformation can bind to RTK or GAB1, promoting catalytic activity. SHP2 dephosphorylates the Ras GTPase-activating protein (RasGAP) binding sites in RTK, preventing RasGAP recruitment to the plasma membrane (133, 134). This negative regulation of RasGAP leads to increase of Ras activity, and thus MAPK signaling. NS and leukemia-associated SHP2 mutants increase MAPK signaling, while LPRD syndrome–associated mutants decrease PTP activity, with both enzymatically activating and inactivating mutations in PTPN11 unexpectedly resulting in neurodevelopmental disorders with overlapping clinical phenotypes (127). PDB, Protein Data Bank.