PTPN11

PTPN11 is a human gene that encodes SHP-2, a non-receptor protein tyrosine phosphatase involved in signal transduction from a variety of receptor and cytokine receptors. SHP-2 plays a key role in regulating cell growth, differentiation, and development by modulating signaling pathways, particularly the Ras/MAPK cascade. The gene is widely expressed in many tissues.

The SHP-2 protein contains two Src homology 2 (SH2) domains and a catalytic protein tyrosine phosphatase (PTP) domain. In its resting state, SHP-2 is autoinhibited by the N-SH2 domain blocking the catalytic site. Binding to phosphotyrosine motifs relieves this autoinhibition and activates phosphatase activity. SHP-2 participates in signaling from receptor tyrosine kinases such as EGFR, PDGFR, FGFR, and others, promoting Ras activation and downstream ERK signaling. It can also influence other pathways in context, including PI3K-AKT and JAK-STAT signaling, depending on cellular context and interacting partners.

Clinical significance includes germline PTPN11 mutations that cause Noonan syndrome and related Rasopathies, characterized by distinctive facial features, congenital heart defects, short stature, and developmental differences. Somatic activating mutations in PTPN11 are found in various hematologic malignancies, notably juvenile myelomonocytic leukemia (JMML), and contribute to dysregulated Ras/MAPK signaling. PTPN11 alterations have made SHP-2 a target of interest for therapeutic development; SHP-2 inhibitors are under investigation as treatments for PTPN11-related diseases and other Ras-pathway cancers, with research examining their potential to normalize signaling in affected cells.