SHP2

Shp-2, or SHP-2, stands for Src homology 2 domain-containing phosphatase 2. It is a ubiquitously expressed non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene in humans. The protein has two N-terminal SH2 domains followed by a C-terminal catalytic phosphatase domain. In its resting state SHP-2 is autoinhibited, with the N-SH2 domain blocking the catalytic site; binding of phosphotyrosine-containing motifs to the SH2 domains relieves this inhibition and activates the enzyme.

Functionally, SHP-2 participates in signaling downstream of many receptor tyrosine kinases and other receptors, and it modulates pathways such as the RAS/MAPK cascade, as well as PI3K-AKT and JAK-STAT in various contexts. By dephosphorylating specific substrates and regulators, SHP-2 helps propagate signals that control cell growth, differentiation, and survival. In many developmental and cellular settings, SHP-2 acts as a positive regulator of MAPK signaling, although its effects can be context-dependent and more complex in some pathways.

Clinical significance is strongly linked to SHP-2’s role in RAS pathway regulation. Germline activating mutations in PTPN11 cause Noonan syndrome and related RASopathies, while somatic PTPN11 mutations appear in juvenile myelomonocytic leukemia (JMML) and other leukemias, as well as various solid tumors. These mutations often affect SHP-2’s catalytic activity or its regulation of signaling, influencing disease phenotype and prognosis.

Therapeutically, SHP-2 has emerged as a drug target in cancers driven by aberrant MAPK signaling. Several allosteric inhibitors have been developed to stabilize SHP-2’s autoinhibited state, including SHP099 and other clinical candidates. These agents are being evaluated in preclinical studies and clinical trials for solid tumors and hematologic malignancies, with the aim of dampening oncogenic signaling and improving treatment outcomes.