Protein tyrosine phosphatase non-receptor type 5 is an enzyme that in humans is encoded by the PTPN5gene.
Protein tyrosine phosphatase (PTP), non-receptor type 5, also known as STEP (STriatal-Enriched protein tyrosine Phosphatase), was the first brain-specific PTP discovered. The human STEP locus maps to chromosome 11p15.2-p15.1 and the murine STEP gene to chromosome 7B3-B5. The single STEP gene is alternatively spliced to produce several isoforms, the best characterized of which are the cytosolic STEP46 protein and the membrane-associated STEP61 protein.
Seven known targets of STEP have been identified as of 2015, including ERK1/2,p38,Fyn,Pyk2,PTPα, and the glutamate receptor subunits GluN2B and GluA2. STEP dephosphorylation of the kinases (ERK1/2, p38, Fyn, and Pyk2) occurs at a regulatory tyrosine within the kinase activation loop and leads to their inactivation. Dephosphorylation of a regulatory tyrosine on PTPα prevents the translocation of PTPα from the cytosol to lipid rafts, where it normally activates Fyn. STEP thereby directly inactivates Fyn and also prevents the translocation of PTPα to compartments where it activates Fyn. STEP dephosphorylation of GluN2B and GluA2 leads to the internalization of NMDARs (GluN1/GluN2B) and AMPARs (GluA1/GluA2). Thus, one function of STEP is to oppose synaptic strengthening by inactivating kinases and internalizing receptors that are critical for the development of synaptic strengthening.
Several STEP inhibitors have now been discovered.GlaxoSmithKline chose STEP as a new project for their Discovery Partnerships with Academia (DPAc) in 2014. This is a relatively new program in drug discovery and brings together the academic world with the drug discovery expertise of GSK to discover new inhibitors of validated targets.
^Li X, Luna J, Lombroso PJ, Francke U (Aug 1995). "Molecular cloning of the human homolog of a striatum-enriched phosphatase (STEP) gene and chromosomal mapping of the human and murine loci". Genomics28 (3): 442–9. doi:10.1006/geno.1995.1173. PMID7490079.
^Sharma E, Zhao F, Bult A, Lombroso PJ (Aug 1995). "Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases". Brain Research. Molecular Brain Research32 (1): 87–93. doi:10.1016/0169-328x(95)00066-2. PMID7494467.
^Bult A, Zhao F, Dirkx R, Sharma E, Lukacsi E, Solimena M, Naegele JR, Lombroso PJ (Dec 1996). "STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum". The Journal of Neuroscience16 (24): 7821–31. PMID8987810.
^Lombroso PJ, Naegele JR, Sharma E, Lerner M (Jul 1993). "A protein tyrosine phosphatase expressed within dopaminoceptive neurons of the basal ganglia and related structures". The Journal of Neuroscience13 (7): 3064–74. PMID8331384.
^Boulanger LM, Lombroso PJ, Raghunathan A, During MJ, Wahle P, Naegele JR (Feb 1995). "Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase". The Journal of Neuroscience15 (2): 1532–44. PMID7869116.
^Legastelois, R; Darcq, E; Wegner, S. A.; Lombroso, P. J.; Ron, D (2015). "Striatal-Enriched Protein Tyrosine Phosphatase Controls Responses to Aversive Stimuli: Implication for Ethanol Drinking". PLOS ONE10 (5): e0127408. doi:10.1371/journal.pone.0127408. PMID25992601.
^Yang CH, Huang CC, Hsu KS (May 2012). "A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes". The Journal of Neuroscience32 (22): 7550–62. doi:10.1523/JNEUROSCI.5902-11.2012. PMID22649233.
Kanamaru H, Asahina K (Oct 1990). "[Venous aneurysm of V. saphena accessoria--a case report]". Nihon Geka Gakkai Zasshi91 (10): 1648–51. PMID2263249.
Li X, Luna J, Lombroso PJ, Francke U (Aug 1995). "Molecular cloning of the human homolog of a striatum-enriched phosphatase (STEP) gene and chromosomal mapping of the human and murine loci". Genomics28 (3): 442–9. doi:10.1006/geno.1995.1173. PMID7490079.
Yoneya T, Yamada Y, Kakeda M, Osawa M, Arai E, Hayashi K, Nishi N, Inoue H, Nishikawa M (Jul 1997). "Molecular cloning of a novel receptor-type protein tyrosine phosphatase from murine fetal liver". Gene194 (2): 241–7. doi:10.1016/S0378-1119(97)00174-1. PMID9272866.