Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN5
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:18,727,928-18,792,721 (from NCBI)
PTPN5 is a brain-specific protein tyrosine phosphatase. It is a component of the N-methyl-D-aspartate receptor (NMDAR; see 138249) complex that regulates NMDAR function in opposition to SRC (190090) at excitatory synapses (Pelkey et al., 2002).
Lombroso et al. (1991) isolated from a rat striatal cDNA library a cDNA clone encoding a neural-specific putative protein-tyrosine phosphatase. RNA analyses of various regions of the rat brain demonstrated a 3-kb and a 4.4-kb mRNA. The 3-kb mRNA was highly enriched within the striatum relative to other brain areas and thus was termed 'striatum-enriched phosphatase' (STEP) by the authors. In contrast, the 4.4-kb message was most abundant in the cerebral cortex and rare in the striatum. These 2 messages appeared to be alternatively processed mRNA transcripts of a single gene.
Sharma et al. (1995) isolated and characterized additional alternatively spliced transcripts of the STEP gene. STEP46 is the full-length, 46-kD protein. STEP20 does not have the conserved tyrosine phosphatase domain. STEP61 has a 5-prime extended open reading frame that encodes a protein with a predicted molecular mass of 61 kD and contains a single tyrosine phosphatase domain.
Li et al. (1995) cloned a human cDNA, which they called STEP, from a fetal brain library using a probe produced by degenerate PCR with primers based on the rat sequence. The 537-amino acid predicted protein is between 85% and 90% identical to the mouse and rat sequences.
By somatic cell hybrid analysis and fluorescence in situ hybridization, Li et al. (1995) mapped the human PTPN5 gene to chromosome 11p15.2-p15.1 and the mouse gene to chromosome 7B3-B5, regions of known homology of synteny.
Gross (2019) mapped the PTPN5 gene to chromosome 11p15.1 based on an alignment of the PTPN5 sequence (GenBank BC064807) with the genomic sequence (GRCh38).
By immunoprecipitation analysis, Pelkey et al. (2002) identified rat Step61 as a component of the NMDAR complex. Step selectively depressed NMDA single-channel activity and NMDAR-mediated synaptic currents of cultured rat neurons by opposing the effect of Src on NMDAR function. Administering Step to CA1 neurons prevented induction of long-term potentiation (LTP) by tetanic stimulation of Schaffer collaterals. Inhibiting endogenous Step in CA1 neurons caused sustained potentiation of excitatory postsynaptic potentials and occluded tetanus-induced LTP in an NMDAR-, Src-, and Ca(2+)-dependent manner.
In rat neuronal cell cultures, Paul et al. (2003) showed that glutamate-mediated activation of NMDARs led to the rapid but transient phosphorylation of extracellular signal-related kinase-2 (ERK2; 176948). NMDA-mediated influx of calcium, but not increased intracellular calcium from other sources, led to activation of the calcium-dependent phosphatase calcineurin and the subsequent dephosphorylation and activation of Step. Step then inactivated Erk2 through dephosphorylation of the tyrosine residue in its activation domain and blocked nuclear translocation of the kinase. Thus, STEP is important in regulating the duration of ERK activation and downstream signaling in neurons.
Dedek et al. (2019) found that Glun2b (GRIN2B; 138252) NMDARs were potentiated at lamina I synapses in a rat model of chronic inflammatory pain, with associated downregulation of synaptic Step61. Glun2b-containing NMDARs were phosphorylated and potentiated by a Kcc2 (SLC12A5; 606726)- and Fyn (137025)-dependent pathway at lamina I synapses, and decreased activity of Step61 was necessary and sufficient to prime phosphorylation and potentiation. Kcc2-dependent disinhibition at lamina I synapses downregulated Step61 and subsequently drove the increase in excitatory Glun2b NMDAR responses, whereas blocking Kcc2-dependent disinhibition prevented it. The authors also characterized GLUN2B-mediated NMDAR responses at human lamina I synapses and validated their observations in the rat model.
Dedek, A., Xu, J., Kandegedara, C. M., Lorenzo, L.-E., Godin, A. G., De Koninck, Y., Lombroso, P. J., Tsai, E. C., Hildebrand, M. E. Loss of STEP-61 couples disinhibition to N-methyl-D-aspartate receptor potentiation in rodent and human spinal pain processing. Brain 142: 1535-1546, 2019. [PubMed: 31135041] [Full Text: https://doi.org/10.1093/brain/awz105]
Gross, M. B. Personal Communication. Baltimore, Md. 10/1/2019.
Li, X., Luna, J., Lombroso, P. J., Francke, U. Molecular cloning of the human homolog of a striatum-enriched phosphatase (STEP) gene and chromosomal mapping of the human and murine loci. Genomics 28: 442-449, 1995. [PubMed: 7490079] [Full Text: https://doi.org/10.1006/geno.1995.1173]
Lombroso, P. J., Murdoch, G., Lerner, M. Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum. Proc. Nat. Acad. Sci. 88: 7242-7246, 1991. [PubMed: 1714595] [Full Text: https://doi.org/10.1073/pnas.88.16.7242]
Paul, S., Nairn, A. C., Wang, P., Lombroso, P. J. NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nature Neurosci. 6: 34-42, 2003. [PubMed: 12483215] [Full Text: https://doi.org/10.1038/nn989]
Pelkey, K. A., Askalan, R., Paul, S., Kalia, L. V., Nguyen, T.-H., Pitcher, G. M., Salter, M. W., Lombroso, P. J. Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation. Neuron 34: 127-138, 2002. [PubMed: 11931747] [Full Text: https://doi.org/10.1016/s0896-6273(02)00633-5]
Sharma, E., Zhao, F., Bult, A., Lombroso, P. J. Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases. Molec. Brain Res. 32: 87-93, 1995. [PubMed: 7494467] [Full Text: https://doi.org/10.1016/0169-328x(95)00066-2]