Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRD
Cytogenetic location: 9p24.1-p23 Genomic coordinates (GRCh38): 9:8,314,246-10,613,002 (from NCBI)
For background information on protein-tyrosine phosphatases (PTPases), see 176884.
By screening a human placenta cDNA library with Drosophila Ptp, Krueger et al. (1990) cloned several PTPases, including a partial PTPRD sequence, which they called PTP-delta. Based on similarity with other PTPases, Krueger et al. (1990) predicted that full-length PTP-delta is about 1,900 amino acids long and that it has an N-terminal signal peptide. The partial clone predicted a protein with several fibronectin (FN1; 135600) type III domains of about 90 amino acids each in the N-terminal region, followed by a transmembrane segment and a cytoplasmic region containing duplicate PTPase-like domains. PTP-delta shares significant similarity with human LAR (PTPRF; 179590).
Mizuno et al. (1993) isolated a mouse gene, which they called Mptp-delta, that is highly homologous to the human protein-tyrosine phosphatase-delta gene isolated by Krueger et al. (1990). The cDNA clones were isolated by screening mouse brain cDNA libraries with mouse CD45 protein-tyrosine phosphatase domain probes under reduced stringency. Northern blot analysis demonstrated expression of 3 mRNA species in brain, kidney, and heart. In situ hybridization of brain samples revealed that the mRNA was present in hippocampus, thalamic reticular nucleus, and piriform cortex. Although this murine mRNA was not detected in lymphoid tissues, all of the pre-B cell lines tested and 1 of 3 B-cell lines tested expressed mRNA, whereas antibody-producing B-cell hybridomas and T-cell and macrophage lines did not.
Testing a panel of recombinant inbred strains, Mizuno et al. (1993) mapped the mouse Ptprd gene to chromosome 4 in tight linkage to the 'brown' (b) locus.
Hartz (2009) mapped the PTPRD gene to chromosome 9p24.1-p23 based on an alignment of the PTPRD sequence (GenBank BCO28O38) with the genomic sequence (GRCh37).
Using the cytoplasmic segment of human PTP-delta expressed in E. coli, Krueger et al. (1990) confirmed that PTP-delta had measurable PTPase activity against phosphorylated test substrates.
Using affinity purification, Takahashi et al. (2012) showed that the extracellular region of Slitrk3 (609679) interacted with PTP-delta with high affinity. The interaction was trans-synaptic at inhibitory synapses, because it took place between Slitrk3 at inhibitory postsynaptic sites and axonal PTP-delta in neurons. Further analysis demonstrated that Slitrk3 induced inhibitory presynaptic differentiation through presynaptic receptor PTP-delta. Slitrk2 (300561) also required trans-interaction with axonal PTP-delta specifically for inhibitory presynaptic differentiation, as different presynaptic receptors for Slitrk2 appeared to exist.
Asprosin is a fasting-induced glucogenic and orexigenic hormone produced by cleavage of profibrillin (FBN1; 134797). Using immunoprecipitation and mass spectrometric analysis, Mishra et al. (2022) identified Ptprd as an asprosin-interacting receptor in mouse brain. Ptprd was expressed in agouti-related protein (AGRP; 602311) neurons of mouse brain and functioned as an orexigenic receptor for asprosin, binding to asprosin with nanomolar affinity through its extracellular domain. Knockdown analysis in HEK293T cells revealed that asprosin activated PTPRD in a cell-autonomous manner.
For discussion of a possible association between variation in the PTPRD gene and restless legs syndrome, see RLS3 (610438).
Ptprd is a receptor-type protein-tyrosine phosphatase expressed in the specialized regions of the brain, including the hippocampal CA2 and CA3, in B lymphocytes, and in the thymic medulla. To elucidate the physiologic roles of Ptprd, Uetani et al. (2000) produced Ptprd-deficient mice by gene targeting. They found that Ptprd-deficient mice were semilethal due to insufficient food intake. The mice also exhibited learning impairment in the Morris water maze, reinforced T-maze, and radial arm maze tasks. Although the histology of the hippocampus appeared normal, the magnitudes of long-term potentiation (LTP) induced at hippocampal CA1 and CA3 synapses were significantly enhanced in Ptprd-deficient mice, with augmented paired-pulse facilitation in the CA1 region. Uetani et al. (2000) concluded that Ptprd plays important roles in regulating hippocampal LTP and learning processes, and that hippocampal LTP does not necessarily positively correlate with spatial learning ability. They stated that Ptprd is an important regulator of synaptic plasticity and discussed the role of Ptprd in learning and memory.
Mishra et al. (2022) found that Ptprd -/- mice were lean and hypophagic compared with wildtype, with significantly lower subcutaneous and intraperitoneal adipose mass. Ptprd -/- mice phenocopied the mouse model of neonatal progeroid syndrome (NPS, or MFLS; 616914), which results from asprosin deficiency. In contrast with whole-body Ptprd -/- mice, where both sexes were equally affected, mice with whole-body loss of a single Ptprd allele or with AGRP neuron-specific loss of both alleles of Ptprd exhibited protection against diet-induced obesity in females. Furthermore, mice with deletion of Ptprd specifically in AGRP neurons were unresponsive to exogenous asprosin, indicating absolute Ptprd necessity for asprosin-mediated AGRP neuron activation. However, Ptprd -/- mice were unresponsive to the orexigenic effects of asprosin, but responded normally to its glucogenic effects, indicating that Ptprd did not mediate the glucogenic effects of asprosin. Ectopic introduction of the Ptprd ligand-binding domain into the circulation of diet-induced obese mice sequestered asprosin to decrease appetite, body weight, and blood glucose, identifying the PTPRD ligand-binding domain as a possible appetite-suppressing therapeutic.
Hartz, P. A. Personal Communication. Baltimore, Md. 10/23/2009.
Krueger, N. X., Streuli, M., Saito, H. Structural diversity and evolution of human receptor-like protein tyrosine phosphatases. EMBO J. 9: 3241-3252, 1990. [PubMed: 2170109] [Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb07523.x]
Mishra, I., Xie, W. R., Bournat, J. C., He, Y., Wang, C., Silva, E. S., Liu, H., Ku, Z., Chen, Y., Erokwu, B. O., Jia, P., Zhao, Z., An, Z., Flask, C. A., He, Y., Xu, Y., Chopra, A. R. Protein tyrosine phosphatase receptor delta serves as the orexigenic asprosin receptor. Cell Metab 34: 549-563, 2022. [PubMed: 35298903] [Full Text: https://doi.org/10.1016/j.cmet.2022.02.012]
Mizuno, K., Hasegawa, K., Katagiri, T., Ogimoto, M., Ichikawa, T., Yakura, H. MPTP-delta, a putative murine homolog of HPTP-delta, is expressed in specialized regions of the brain and in the B-cell lineage. Molec. Cell. Biol. 13: 5513-5523, 1993. [PubMed: 8355697] [Full Text: https://doi.org/10.1128/mcb.13.9.5513-5523.1993]
Takahashi, H., Katayama, K., Sohya, K., Miyamoto, H., Prasad, T., Matsumoto, Y., Ota, M., Yasuda, H., Tsumoto, T., Aruga, J., Craig, A. M. Selective control of inhibitory synapse development by Slitrk3-PTP-delta trans-synaptic interaction. Nature Neurosci. 15: 389-398, 2012. [PubMed: 22286174] [Full Text: https://doi.org/10.1038/nn.3040]
Uetani, N., Kato, K., Ogura, H., Mizuno, K., Kawano, K., Mikoshiba, K., Yakura, H., Asano, M., Iwakura, Y. Impaired learning with enhanced hippocampal long-term potentiation in PTP-delta-deficient mice. EMBO J. 19: 2775-2785, 2000. [PubMed: 10856223] [Full Text: https://doi.org/10.1093/emboj/19.12.2775]