Protein tyrosine phosphatase non-receptor type 11 (PTPN11) (SHP2)

Protein tyrosine phosphatase non-receptor type 11 (PTPN11), widely known as SHP2, is a non-receptor protein tyrosine phosphatase that functions as a critical signaling node downstream of various receptor tyrosine kinases (UniProt P35235). It is composed of two N-terminal SH2 domains and a catalytic PTP domain, existing in an auto-inhibited "closed" state until activated by binding to phosphotyrosine-containing proteins (PubMed: 30103424). SHP2 is essential for the activation of the RAS/MAPK pathway, which regulates fundamental cellular processes such as proliferation, differentiation, and survival (PubMed: 32034355). In many cancers, wild-type SHP2 is required to sustain oncogenic signaling driven by upstream mutations in receptors like EGFR or downstream mutations in KRAS. Because of its central role in these pathways, SHP2 has become a high-priority target for small-molecule drug development in oncology. Current therapeutic strategies focus on allosteric inhibitors that stabilize the inactive conformation of the enzyme, effectively blocking the signal transduction required for tumor growth (PubMed: 31978346). These inhibitors are being evaluated both as monotherapies and in combination with other targeted agents to overcome drug resistance in various solid tumors and hematological malignancies (ClinicalTrials.gov).

Other names

PTPN11SH-PTP2SH-PTP3PTP2CSAP2BPTP3CFCNS1

Allosteric inhibition by stabilizing the auto-inhibited (closed) conformation of the enzyme, preventing its activation by phosphoprotein binding and subsequent signaling through the RAS/MAPK pathway.