Protein tyrosine phosphatase non-receptor type 5 (PTPN5)

Protein tyrosine phosphatase non-receptor type 5 (PTPN5), commonly called striatal-enriched protein tyrosine phosphatase (STEP), is a brain-specific enzyme that regulates synaptic function and plasticity through dephosphorylation of key neuronal proteins, such as NMDA and AMPA glutamate receptors and various kinases including ERK1/2, p38, Fyn, and Pyk2. STEP acts as a negative regulator of synaptic strengthening by inactivating signaling proteins and promoting internalization of glutamate receptors, thereby opposing long-term potentiation. Dysregulation of STEP expression or activity has been linked to several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Fragile X syndrome, supporting its role as a therapeutic target. Current drug discovery efforts aim to develop selective STEP modulators (inhibitors or activators), though significant selectivity and bioavailability issues remain due to the highly conserved and charged nature of its active site, as well as the complexity of its regulation by post-translational modifications and oxidative mechanisms.

Other names

STEPSTEP61Striatal-enriched protein tyrosine phosphataseNeural-specific protein-tyrosine phosphataseProtein tyrosine phosphatase striatum-enrichedPTPSTEPProtein-tyrosine phosphatase non-receptor type 5PTP-SL

Inhibition or activation of STEP can alter phosphorylation states of neuronal signaling proteins, modulate synaptic strength, and affect glutamate receptor trafficking; small-molecule inhibitors block dephosphorylation activity, while allosteric activators increase phosphatase function