SH2 domain-containing protein tyrosine phosphatase 2 (SHP2)

SH2 domain-containing protein tyrosine phosphatase 2 (SHP2, encoded by the PTPN11 gene) is a widely expressed, non-receptor protein tyrosine phosphatase that integrates signals from various membrane-bound receptors, including receptor tyrosine kinases, cytokine receptors, and immune checkpoints[4][5][3]. The protein contains two SH2 domains (N-terminal and C-terminal), a catalytic protein tyrosine phosphatase domain, and a C-terminal tail region. SHP2 is critical in positive signal transduction from activated growth factor and immune receptors, regulating multiple downstream pathways such as RAS-RAF-MEK-ERK (MAPK), PI3K-AKT, and JAK-STAT, which control cell growth, differentiation, survival, migration, and immune response[3][4][5][6]. Gain-of-function mutations in PTPN11 drive several cancers, especially juvenile myelomonocytic leukemia, and underlie Noonan syndrome and related developmental disorders[3][4]. Aberrant SHP2 activity promotes the progression of many solid tumors and mediates resistance to targeted cancer therapy[4][6]. SHP2 also has distinct roles in immune regulation, including regulation of T-cell receptor signaling and immune checkpoints like PD-1[6][7]. Multiple allosteric SHP2 inhibitors are in clinical development targeting its enzymatic and scaffolding functions, mostly for oncology indications[4][6].

Other names

SHP2Protein tyrosine phosphatase non-receptor type 11PTPN11SH2 domain-containing phosphatase 2Src homology 2 domain-containing phosphatase 2

Allosteric inhibition (stabilizing inactive conformation of SHP2); Blocking SHP2’s catalytic activity; Disrupting SHP2 protein–protein interactions[3]