SHP2
OVERVIEW
Src homology region 2 domain-containing phosphatase 2 (SHP2), also known as tyrosine-protein phosphatase non-receptor type 11 (PTPN11) is a ubiquitously expressed non-receptor tyrosine phosphatase that mediates cellular signaling through the RAS-ERK pathway.1 SHP2 is activated upon interaction of the N-terminal SH2 domains with phosphorylated cell surface receptors (e.g., pRTKs, pPD-1, etc.) to transduce extracellular signals.2
IMPLICATIONS IN CANCER
Many tumors have genetic mutations, driving abnormal cancer cell growth which relies on SHP2 activity.1 SHP2 regulates survival and proliferation primarily via the RAS-ERK pathway, specifically RTK, NF1 loss, RAS, Class-III RAF-driven cancers depend on SHP2.1 SHP2 also plays a key role to control cytokine production and immune cell response. SHP2 is implicated in immune evasion via the PD-1 and BTLA immune checkpoint pathways.2 Therefore, inhibition of SHP2 is believed to have dual effects by potentially reducing cancer cell growth and modulating immune responses to generate anti-tumor activities.3
- Neel BG, et al. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28: 284–293.
- Marasco M, et al. Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci Adv. 2020;6(5):4458.
- Wang P, et al. Investigation of KRAS G12C inhibitor JAB-21822 as a single agent and in combination with SHP2 inhibitor JAB-3312 in preclinical cancer models. Ann Oncol. 2022;33(9):S1441.
