Protein tyrosine phosphatase non-receptor type 11 (SHP2) E76K mutant (SHP2 E76K)

Protein tyrosine phosphatase non-receptor type 11 (SHP2), encoded by the PTPN11 gene, is a critical signaling node that mediates signal transduction from multiple receptor tyrosine kinases to the RAS/MAPK pathway [1]. The E76K mutation is a potent gain-of-function alteration located in the N-SH2 domain that disrupts the natural auto-inhibitory interaction with the catalytic PTP domain, leading to constitutive phosphatase activity [2]. This hyperactivation drives aberrant cell growth and survival, making it a primary driver in juvenile myelomonocytic leukemia (JMML) and a significant contributor to various solid tumors [3]. Modern therapeutic approaches utilize allosteric inhibitors that bind to a pocket formed by the three domains of SHP2, locking the protein in an inactive "closed" state and preventing the activation of downstream oncogenic signaling [4]. These inhibitors, such as TNO155 and RMC-4630, are currently being investigated in clinical trials as targeted therapies for patients harboring PTPN11 mutations or as combination partners to overcome resistance to other MAPK-targeted agents [5].

Other names

PTPN11 E76KSH-PTP2 E76KSH-PTP3 E76KSyp E76KPTP2C E76KPTP-1D E76K

Allosteric inhibition by binding to a central tunnel formed by the N-SH2, C-SH2, and PTP domains, thereby stabilizing the enzyme in its inactive, auto-inhibited conformation.