Dual specificity phosphatase 6 (DUSP6) (DUSP6)

Dual specificity phosphatase 6 (DUSP6), also known as MKP3, is a member of the mitogen-activated protein kinase (MAPK) phosphatase family that specifically inactivates ERK1 and ERK2 (Source: UniProt Q16828). It functions as a feedback regulator of the RAS/ERK pathway, where its expression is often induced by ERK signaling to maintain pathway homeostasis (Source: PubMed 25154351). The kinase-binding domain (KBD) at the N-terminus is critical for substrate recognition and specificity, mediating the interaction with the docking site on ERK (Source: PubMed 11003654). In oncology, DUSP6 is frequently overexpressed in cancers driven by the MAPK pathway, such as pancreatic and lung adenocarcinoma, where it may promote cell survival or contribute to drug resistance (Source: PubMed 28655770). Small molecule inhibitors like BCI (E-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one) target the DUSP6 KBD/catalytic interface to allosterically inhibit its activity, leading to increased ERK phosphorylation and potential anti-tumor effects (Source: PubMed 19114708).

Other names

MKP3Mitogen-activated protein kinase phosphatase 3PYST1Dual specificity protein phosphatase 6

Allosteric inhibition of the phosphatase activity by binding to the kinase-binding domain or the interface between the KBD and the catalytic domain, preventing the dephosphorylation of ERK1/2.