Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRS
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:5,205,508-5,340,812 (from NCBI)
Protein-tyrosine phosphatase sigma (PTPRS) is a receptor type protein-tyrosine phosphatase that has been cloned and identified in mouse, in rat, and in human (Pulido et al., 1995).
Wang et al. (1995) studied the expression of PTPRS in rat tissues. Northern blot analysis revealed that a 6.9-kb transcript was more abundant during embryonic development, whereas a 5.7-kb transcript was more abundant during postnatal development and in the adult. In situ hybridization revealed that RPTPS mRNA was widely expressed throughout the central and peripheral nervous system during embryonic development. The level of expression decreased in most brain regions during postnatal development, but remained high in the hippocampus. Emulsion autoradiography showed that the majority of RPTPS mRNA is expressed in neurons.
PTPRS is a member of a subfamily of receptor type PTPases that includes LAR (PTPRF; 179590) and PTP-delta. Wagner et al. (1996) noted that this subfamily of cell surface glycoproteins is characterized by the presence of an extracellular cell adhesion molecule-like motif and 2 intracellular phosphatase domains. Transcripts of these genes are subject to RNA processing, resulting in several distinct isoforms. These proteins share a high overall degree of sequence similarity, especially in the second intracellular catalytic domain, which is thought to interact with the same molecule.
Batt et al. (2002) examined the role of PTP on pituitary, pancreas, and enteroendocrine cytodifferentiation, hormone production, and development. The adenohypophyses of PTPRS-null mice were small and exhibited reduced GH (see 139250) and PRL (176760) immunoreactivity. Cells containing TSH (see 188540), LH (see 152780), FSH (see 136530), ACTH, pituitary-specific POU homeodomain factor (Pit1; 173110), estrogen receptor (see 133430), and steroidogenic factor-1 (184757) were found in normal proportions and distributions. The diminished expression of GH and PRL was not associated with apoptosis of somatotrophs or lactotrophs. In the knockout mice, pancreatic islets were hypoplastic with reduced insulin immunoreactivity, and there was also variable expression of gut hormones. Functionally, the GH deficiency was associated with hypoglycemia and death in the PTPRS-null neonates, and accordingly, intraperitoneal administration of GH rescued the PTPRS-null neonates and normalized the blood glucose. The authors concluded that PTP-sigma plays a major role in differentiation and development of the neuroendocrine system.
Shen et al. (2009) demonstrated that the transmembrane protein tyrosine phosphatase PTP-sigma binds with high affinity to neural chondroitin sulfate proteoglycans (CSPGs; see 155760). Binding involves the chondroitin sulfate chains and a specific site on the first immunoglobulin-like domain of PTP-sigma. In culture, PTP-sigma-null neurons show reduced inhibition by CSPG. A PTP-sigma fusion protein probe can detect cognate ligands that are upregulated specifically at neural lesion sites. After spinal cord injury, PTPRS gene disruption enhanced the ability of axons to penetrate regions containing CSPG. Shen et al. (2009) concluded that PTP-sigma can act as a receptor for chondroitin sulfate proteoglycans and may provide new therapeutic approaches to neural regeneration.
Coles et al. (2011) reported that RPTP-sigma, also known as PTPRS, acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG (142460) growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTP-sigma ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTP-sigma and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. Coles et al. (2011) concluded that their results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor.
Lang et al. (2015) found in rats that Ptprs has a critical role in converting growth cones of sensory neurons into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. The authors generated a membrane-permeable peptide mimetic of the PTPRS wedge domain that binds to PTPRS and relieves CSPG-mediated inhibition. In rats who had undergone contusive spinal cord injury, systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Lang et al. (2015) concluded that their results added a layer of understanding to the critical role of PTPRS in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.
Wagner et al. (1996) used a murine cDNA of Ptprs as a hybridization probe for genetic mapping of the human homolog, PTPRS. By fluorescence in situ hybridization analysis, they showed that PTPRS maps to chromosome 19p13.3. Hybridization analysis of chromosome 19 library cosmids revealed several positive clones that are part of a contig located in the same region. In addition, the location of this gene relative to previously mapped proximal markers revealed a new point in the human-mouse synteny map by extending the mouse chromosome 17 synteny region in the telomeric direction.
On the basis of its expression and homology with the Drosophila melanogaster orthologs, which have roles in the targeting of axonal growth cones, Elchebly et al. (1999) hypothesized that PTP-sigma may also have a modulating function in cell-cell interactions, as well as in axon guidance during mammalian embryogenesis. To investigate its function in vivo, they generated Ptprs-deficient mice. The resulting Ptprs -/- animals displayed retarded growth, increased neonatal mortality, hyposmia, and hypofecundity. Anatomic and histologic analyses showed a decrease in overall brain size with severe depletion of luteinizing hormone-releasing hormone (152760)-immunoreactive cells in the hypothalamus of the Ptprs -/- mice. These mice also had an enlarged intermediate pituitary lobe, but smaller anterior and posterior lobes. These results suggested that tyrosine phosphorylation-dependent signaling pathways regulated by PTP-sigma influence the proliferation and/or adhesiveness of various cell types in the developing hypothalamopituitary axis.
Wallace et al. (1999) likewise inactivated the Ptprs gene in mice by gene targeting. They found that all Ptprs +/- mice developed normally, whereas 60% of Ptprs -/- mice died within 48 hours after birth. The surviving homozygous Ptprs -/- mice demonstrated stunted growth, developmental delays, and severe neurologic defects including spastic movements, tremor, ataxic gait, abnormal limb flexion, and defective proprioception. Histopathology of brain sections showed reduction and hypocellularity of the posterior pituitary of the homozygous deficient mice, as well as a reduction of approximately 50 to 75% in the number of choline acetyltransferase-positive cells in the forebrain. Moreover, peripheral nerve electrophysiologic analysis revealed slower conduction velocity in the homozygous deficient mice relative to wildtype or heterozygous animals, associated with an increased proportion of slowly conducting, small-diameter myelinated fibers and relative hypomyelination. By approximately 3 weeks of age, most remaining homozygous deficient mice died from a wasting syndrome with atrophic intestinal villi. These results suggested that PTP-sigma has a role in neuronal and epithelial development in mice.
Uetani et al. (2009) obtained late Ptprs/Ptprf double-knockout mouse embryos at the expected mendelian ratio, but none survived to 4 weeks of age, likely due to lethality of Ptprs knockout. At embryonic day 18.5, double-knockout embryos showed severe craniofacial defects, including exencephaly, micrognathia, and failure of eyelid closure. Additional malformation of the eye included hyperplastic inner nuclear layers, persistence of prominent hyaloid arteries, abnormal retrolental tissues, and disorganized neural retina. Double-knockout embryos also showed striking abnormalities of the urinary tract, such as hydroureters, hydronephrosis, duplicated ureter/renal systems, and ureterocele. Absence of Ptprs and Ptprf activity prevented normal execution of the apoptotic program necessary for regression of the common nephric duct during development, resulting in inappropriate tissue survival and delayed distal ureter maturation. In cell culture, Ptprs bound and negatively regulated the phosphorylation and signaling of the Ret receptor tyrosine kinase (164761), whereas Ptprs-induced apoptosis was inhibited by Ret expression. Uetani et al. (2009) concluded that ureter positioning is controlled by the opposing actions of RET and LAR family phosphatases regulating apoptosis-mediated tissue morphogenesis.
Batt, J., Asa, S., Fladd, C., Rotin, D. Pituitary, pancreatic and gut neuroendocrine defects in protein tyrosine phosphatase-sigma-deficient mice. Molec. Endocr. 16: 155-169, 2002. [PubMed: 11773446] [Full Text: https://doi.org/10.1210/mend.16.1.0756]
Coles, C. H., Shen, Y., Tenney, A. P., Siebold, C., Sutton, G. C., Lu, W., Gallagher, J. T., Jones, E. Y., Flanagan, J. G., Aricescu, A. R. Proteoglycan-specific molecular switch for RPTP-sigma clustering and neuronal extension. Science 332: 484-488, 2011. [PubMed: 21454754] [Full Text: https://doi.org/10.1126/science.1200840]
Elchebly, M., Wagner, J., Kennedy, T. E., Lanctot, C., Michaliszyn, E., Itie, A., Drouin, J., Tremblay, M. L. Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nature Genet. 21: 330-333, 1999. [PubMed: 10080191] [Full Text: https://doi.org/10.1038/6859]
Lang, B. T., Cregg, J. M., DePaul, M. A., Tran, A. P., Xu, K., Dyck, S. M, Madalena, K. M., Brown, B. P., Weng, Y.-L., Li, S., Karimi-Abdolrezaee, S., Busch, S. A., Shen, Y., Silver, J. Modulation of the proteoglycan receptor PTP-sigma promotes recovery after spinal cord injury. Nature 518: 404-408, 2015. [PubMed: 25470046] [Full Text: https://doi.org/10.1038/nature13974]
Pulido, R., Serra-Pages, C., Tang, M., Streuli, M. The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proc. Nat. Acad. Sci. 92: 11686-11690, 1995. [PubMed: 8524829] [Full Text: https://doi.org/10.1073/pnas.92.25.11686]
Shen, Y., Tenney, A. P., Busch, S. A., Horn, K. P., Cuascut, F. X., Liu, K., He, Z., Silver, J., Flanagan, J. G. PTP-sigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326: 592-596, 2009. [PubMed: 19833921] [Full Text: https://doi.org/10.1126/science.1178310]
Uetani, N., Bertozzi, K., Chagnon, M. J., Hendriks, W., Tremblay, M. L., Bouchard, M. Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases. J. Clin. Invest. 119: 924-935, 2009. [PubMed: 19273906] [Full Text: https://doi.org/10.1172/JCI37196]
Wagner, J., Gordon, L. A., Heng, H. H. Q., Tremblay, M. L., Olsen, A. S. Physical mapping of receptor type protein tyrosine phosphatase sigma (PTPRS) to human chromosome 19p13.3. Genomics 38: 76-78, 1996. [PubMed: 8954782] [Full Text: https://doi.org/10.1006/geno.1996.0594]
Wallace, M. J., Batt, J., Fladd, C. A., Henderson, J. T., Skarnes, W., Rotin, D. Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTP-sigma. Nature Genet. 21: 334-338, 1999. [PubMed: 10080192] [Full Text: https://doi.org/10.1038/6866]
Wang, H., Yan, H., Canoll, P. D., Silvennoinen, O., Schlessinger, J., Musacchio, J. M. Expression of receptor protein tyrosine phosphatase-sigma (RPTP-sigma) in the nervous system of the developing and adult rat. J. Neurosci. Res. 41: 297-310, 1995. [PubMed: 7563223] [Full Text: https://doi.org/10.1002/jnr.490410303]