Tyrosine-protein phosphatase non-receptor type 5 (PTPN5)

Tyrosine-protein phosphatase non-receptor type 5 (PTPN5), commonly known as striatal-enriched protein tyrosine phosphatase (STEP), is a brain-specific enzyme primarily expressed in the striatum, cortex, and hippocampus [1, 2]. It serves as a critical negative regulator of synaptic plasticity and cognitive function by dephosphorylating and inactivating key signaling proteins such as ERK1/2, p38, and the Src family kinase Fyn [2, 3, 9]. Furthermore, PTPN5 promotes the internalization of NMDA and AMPA glutamate receptors, thereby opposing the development of synaptic strengthening [2, 9]. Dysregulation of PTPN5 is implicated in various neurological conditions; elevated levels are associated with Alzheimer's disease, schizophrenia, and Fragile X syndrome, while reduced levels are observed in Huntington's disease and cerebral ischemia [2, 5, 9]. Consequently, PTPN5 is a significant therapeutic target, with research focusing on small-molecule inhibitors like TC-2153 to restore cognitive function in neurodegenerative states [3, 11]. However, the high structural conservation of the phosphatase catalytic domain presents challenges for achieving drug selectivity and avoiding off-target effects [3, 12]. Recent structural studies have also identified allosteric sites that may allow for the development of more selective modulators [12, 14]. Overall, PTPN5 represents a key node in neuronal signaling whose precise modulation could offer therapeutic benefits across a range of CNS disorders.

Other names

Striatal-enriched protein tyrosine phosphataseSTEPPTPSTEPSTEP61STEP46Neural-specific protein-tyrosine phosphataseStriatum-enriched protein-tyrosine phosphatase

Inhibition of PTPN5 activity to prevent the internalization of glutamate receptors and restore synaptic signaling in neurodegenerative and neuropsychiatric conditions, or activation to modulate excitotoxicity in Huntington's disease.