Alternative titles; symbols
HGNC Approved Gene Symbol: PDPN
Cytogenetic location: 1p36.21 Genomic coordinates (GRCh38): 1:13,583,757-13,617,957 (from NCBI)
By screening a lung cDNA library using rat T1a as probe, Ma et al. (1998) cloned human T1A, which they designated T1A2. The deduced 162-amino acid T1A2 protein contains a putative transmembrane region, a protein kinase A (see 176911) phosphorylation site, and a protein kinase C (see 176960) phosphorylation site. Northern blot analysis detected a 1.2-kb T1A2 transcript only in lung. Ma et al. (1998) also identified a potential T1A variant, which they called T1A1.
Zimmer et al. (1999) identified several cDNAs encoding the human homolog of mouse gp38, rat gp40, and dog gp40, and by 5-prime RACE and RT-PCR of placenta mRNA, they cloned full-length GP36. The deduced 162-amino acid protein is a typical type I membrane glycoprotein, with an N-terminal signal sequence, a signal sequence cleavage site, a C-terminal hydrophobic stretch, and a short cytoplasmic tail. It also contains 31 potential O-glycosylation sites. Most sequence conservation between the human, rat, mouse, and dog proteins resides in the C-terminal tail, and 15 O-glycosylation sites are conserved in all 4 species. GP36 has a calculated molecular mass of 17.8 kD, and the predicted mature protein has a calculated molecular mass of 15.6 kD. PCR analysis detected GP36 transcripts in placenta, lung, skeletal muscle, and heart. Expression was weaker in brain, kidney, and liver, and was not detected in pancreas. Western blot analysis of transfected canine kidney cells recognized a major protein of 36 kD and minor proteins of about 28 and 70 kD. GP36 was expressed on the cell surface. Immunohistochemical analysis of GP36 in placenta, kidney, lung, and nasal polyps showed expression at the apical plasma membrane of vascular endothelial cells and in alveolar epithelial cells.
Schacht et al. (2003) found that mouse T1a was expressed in the cardinal vein and in budding Prox1 (601546)-positive lymphatic progenitor cells between embryonic days 10.5 and 11.5. Expression became restricted to lymphatic endothelium during later development. Ultrastructural analysis revealed prominent localization to the luminal plasma membrane of lymphatic vessels.
Schacht et al. (2003) found that overexpression of rat T1a in human and rodent endothelial cells promoted formation of elongated cell extensions and significantly increased endothelial cell adhesion, migration, and tube formation. Inhibition of T1A expression by small interfering RNAs decreased cell adhesion in cultured human dermal lymphatic endothelial cells.
Kato et al. (2003) determined that T1A2/GP36 is identical to the mouse platelet aggregation-inducing factor Aggrus. Using a platelet aggregation-neutralizing antibody, they identified a platelet aggregation (PLAG) domain in mouse and human T1A2. Mutation of threonine residues in the PLAG domain abolished induction of platelet aggregation. Kato et al. (2003) also found that T1A2 expression was increased in almost all human intestinal tumors (colon, rectum, and small intestine) tested compared with corresponding normal tissues.
Herzog et al. (2013) reported a role for the transmembrane O-glycoprotein PDPN in maintaining high endothelial venule (HEV) barrier function. Mice with postnatal deletion of Pdpn lost HEV integrity and exhibited spontaneous bleeding in mucosal lymph nodes, and bleeding in the draining peripheral lymph nodes after immunization. Blocking lymphocyte homing rescued bleeding, indicating that PDPN is required to protect the barrier function of HEVs during lymphocyte trafficking. Further analyses demonstrated that PDPN expressed on fibroblastic reticular cells, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor-2 (CLEC2; 606783). Mice lacking fibroblastic reticular cell Pdpn or platelet Clec2 exhibited significantly reduced levels of VE-cadherin (CDH5; 601120), which is essential for overall vascular integrity, on HEVs. Infusion of wildtype platelets restored HEV integrity in Clec2-deficient mice. Activation of CLEC2 induced release of sphingosine-1-phosphate (S1PR1; 601974) from platelets, which promoted expression of VE-cadherin on HEVs ex vivo. Furthermore, the draining peripheral lymph nodes of immunized mice lacking S1pr1 had impaired HEV integrity similar to Pdpn- and Clec2-deficient mice. Herzog et al. (2013) concluded that S1PR1 release after PDPN/CLEC2-mediated platelet activation is critical for HEV integrity during immune responses.
Acton et al. (2014) reported that the physical elasticity of lymph nodes is maintained in part by PDPN signaling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC2 expressed on dendritic cells. Acton et al. (2014) showed in mouse cells that Pdpn induces actomyosin contractility in FRCs via activation of RhoA (165390)/ RhoC (165380) and downstream Rho-associated protein kinase (ROCK1; 601702). Engagement by Clec2 causes Pdpn clustering and rapidly uncouples Pdpn from RhoA/RhoC activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of Clec2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking Clec2 expression in dendritic cells. Acton et al. (2014) concluded that the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes also initiate remodeling of lymph nodes by delivering CLEC2 to FRCs. CLEC2 modulation of PDPN signaling permits FRC network stretching and allows for the rapid lymph node expansion, driven by lymphocyte influx and proliferation, that is the critical hallmark of adaptive immunity.
Using RNA and protein expression profiling at single-cell resolution in mouse cells, Chihara et al. (2018) identified a module of coinhibitory receptors that includes not only several known coinhibitory receptors but many novel surface receptors. Chihara et al. (2018) functionally validated 2 novel coinhibitory receptors, activated protein C receptor (PROCR; 600646) and podoplanin. The module of coinhibitory receptors is coexpressed in both CD4+ and CD8+ T cells and is part of a larger coinhibitory gene program that is shared by nonresponsive T cells in several physiologic contexts and is driven by the immunoregulatory cytokine IL27. Computational analysis identified the transcription factors PRDM1 (603423) and c-MAF (177075) as cooperative regulators of the coinhibitory module, and this was validated experimentally. This molecular circuit underlies the coexpression of coinhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumor immunity.
The International radiation Hybrid mapping consortium mapped the T1A gene to chromosome 1 (SHGC-74231).
Schacht et al. (2003) found that T1a-null mice died at birth due to respiratory failure. These mice showed defects in lymphatic vessel pattern formation, but not in blood vessel pattern formation. The defects were associated with diminished lymphatic transport, congenital lymphedema, and dilation of cutaneous and intestinal lymphatic vessels.
Douglas et al. (2009) reported that Pdpn-knockout mice showed hypoplasia of the myocardial sleeve of the pulmonary veins, dorsal atrial wall, and atrial septum. The atrial septum and right-sided wall of the pulmonary vein almost lacked interposed mesenchyme. Extension of smooth muscle cells into the left atrial body was diminished. Douglas et al. (2009) concluded that myocardium of the pulmonary veins, dorsal atrial wall, and atrial septum, as well as the smooth muscle cells, are derived from the posterior heart field regulated by Pdpn.
Peters et al. (2015) found that deletion of Pdpn caused exaggerated T-cell responses and spontaneous experimental autoimmune encephalomyelitis (EAE) in mice with a susceptible genetic background. T cell-specific Pdpn overexpression resulted in profound defects in Il7 (146660)-mediated T-cell expansion and survival, leading to more rapid resolution of central nervous system (CNS) inflammation, characterized by a reduced effector Cd4 (186940)-positive T-cell population in CNS. In contrast, mice with T cell-specific Pdpn deletion developed exacerbated EAE with increased Cd4-positive T cells in CNS. Transcriptional profile analysis of naturally occurring Pdpn-positive effector T cells in mouse CNS revealed increased expression of inhibitory receptors, such as Pd1 (PDCD1; 600244) and Tim3 (HAVCR2; 606652), and decreased expression of prosurvival factors, such as Il7ra (146661). Peters et al. (2015) proposed that PDPN functions as an inhibitory molecule on T cells that promotes tissue tolerance by preventing long-term survival and maintenance of CD4-positive effector T cells in target organs.
Acton, S. E., Farrugia, A. J., Astarita, J. L., Mourao-Sa, D., Jenkins, R. P., Nye, E., Hooper, S., van Blijswijk, J., Rogers, N. C., Snelgrove, K. J., Rosewell, I., Moita, L. F., Stamp, G., Turley, S. J., Sahai, E., Reis e Sousa, C. Dendritic cells control fibroblastic reticular network tension and lymph node expansion. Nature 514: 498-502, 2014. [PubMed: 25341788] [Full Text: https://doi.org/10.1038/nature13814]
Chihara, N., Madi, A., Kondo, T., Zhang, H., Acharya, N., Singer, M., Nyman, J., Marjanovic, N. D., Kowalczyk, M. S., Wang, C., Kurtulus, S., Law, T., and 9 others. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558: 454-459, 2018. [PubMed: 29899446] [Full Text: https://doi.org/10.1038/s41586-018-0206-z]
Douglas, Y. L., Mahtab, E. A. F., Jongbloed, M. R. M., Uhrin, P., Zaujec, J., Binder, B. R., Schalij, M. J., Poelmann, R. E., Deruiter, M. C., Gittenberger-de Groot, A. C. Pulmonary vein, dorsal atrial wall and atrial septum abnormalities in Podoplanin knockout mice with disturbed posterior heart field contribution. Pediat. Res. 65: 27-32, 2009. [PubMed: 18784615] [Full Text: https://doi.org/10.1203/PDR.0b013e31818bc11a]
Herzog, B. H., Fu, J., Wilson, S. J., Hess, P. R., Sen, A., McDaniel, M., Pan, Y., Sheng, M., Yago, T., Silasi-Mansat, R., McGee, S., May, F., Nieswandt, B., Morris, A. J., Lupu, F., Coughlin, S. R., McEver, R. P., Chen, H., Kahn, M. L., Xia, L. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502: 105-109, 2013. [PubMed: 23995678] [Full Text: https://doi.org/10.1038/nature12501]
Kato, Y., Fujita, N., Kunita, A., Sato, S., Kaneko, M., Osawa, M., Tsuruo, T. Molecular identification of Aggrus/T1-alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J. Biol. Chem. 278: 51599-51605, 2003. [PubMed: 14522983] [Full Text: https://doi.org/10.1074/jbc.M309935200]
Ma, T., Yang, B., Matthay, M. A., Verkman, A. S. Evidence against a role of mouse, rat, and two cloned human T1-alpha isoforms as a water channel or a regulator of aquaporin-type water channels. Am. J. Resp. Cell Molec. Biol. 19: 143-149, 1998. [PubMed: 9651190] [Full Text: https://doi.org/10.1165/ajrcmb.19.1.2953]
Peters, A., Burkett, P. R., Sobel, R. A., Buckley, C. D., Watson, S. P., Bettelli, E., Kuchroo, V. K. Podoplanin negatively regulates CD4+ effector T cell responses. J. Clin. Invest. 125: 129-139, 2015. [PubMed: 25415436] [Full Text: https://doi.org/10.1172/JCI74685]
Schacht, V., Ramirez, M. I., Hong, Y.-K., Hirakawa, S., Feng, D., Harvey, N., Williams, M., Dvorak, A. M., Dvorak, H. F., Oliver, G., Detmar, M. T1-alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22: 3546-3556, 2003. [PubMed: 12853470] [Full Text: https://doi.org/10.1093/emboj/cdg342]
Zimmer, G., Oeffner, F., von Messling, V., Tschernig, T., Grone, H.-J., Klenk, H.-D., Herrler, G. Cloning and characterization of gp36, a human mucin-type glycoprotein preferentially expressed in vascular endothelium. Biochem. J. 341: 277-284, 1999. [PubMed: 10393083]