Protein tyrosine phosphatase non-receptor type 6 and Protein tyrosine phosphatase non-receptor type 11 (SHP1 and SHP2)

Protein tyrosine phosphatase non-receptor type 6 (SHP1) and type 11 (SHP2) are closely related cytoplasmic enzymes characterized by two N-terminal Src homology 2 (SH2) domains and a C-terminal catalytic domain. SHP2 (PTPN11) is a well-established oncogenic driver that positively regulates the Ras-MAPK pathway and is frequently mutated in Noonan syndrome and various malignancies, including leukemia and solid tumors. In contrast, SHP1 (PTPN6) is primarily expressed in hematopoietic cells and typically functions as a negative regulator of immune signaling, often acting as a tumor suppressor by dephosphorylating activating kinases. Both phosphatases are recruited to inhibitory receptors such as PD-1 and BTLA, making them critical nodes in immune checkpoint signaling and attractive targets for cancer immunotherapy. Therapeutic development has largely focused on allosteric SHP2 inhibitors that lock the enzyme in its inactive, autoinhibited conformation to overcome the challenges of targeting the highly conserved catalytic site. While SHP2 inhibition is a promising strategy for treating RAS-driven cancers, the functional redundancy and opposing roles of SHP1 and SHP2 in certain contexts necessitate careful selective targeting to avoid adverse effects on hematopoiesis and immune homeostasis.

Other names

SHP-1SHP-2PTPN6PTPN11SH-PTP1SH-PTP2PTP1CPTP1DHCPPTP2CBPTP3CFCNS1

Allosteric inhibition (stabilizing the autoinhibited conformation), catalytic site inhibition, and modulation of protein-protein interactions via SH2 domains.