PDPN explained

Podoplanin is a protein that in humans is encoded by the PDPN gene.^{[1] [2] [3]}

Structure and function

Podoplanin is a mucin-type protein with a mass of 36- to 43-kDa. It is relatively well conserved between species, with homologues in humans, mice, rats, dogs and hamsters.^[4]

This gene encodes a type-I, integral membrane, heavily O-glycosylated glycoprotein with diverse distribution in human tissues. The physiological function of this protein may be related to its mucin-type character. The homologous protein in other species has been described as a differentiation antigen and influenza-virus receptor. The specific function of this protein has not been determined but it has been proposed as a marker of lung injury. Alternatively spliced transcript variants encoding different isoforms have been identified.

This protein has been found to have functions in lung alveolar cells, kidney podocytes, and lymphatic endothelial cells. More recently, this protein has been found in neural tissue in both mouse and human samples.^[5]

In lymphatic endothelial cells, experimentation has indicated that podoplanin plays a role in proper formation of linkages between the cardiovascular system and the lymphatic systems, typically causing fatty liver disease in these mice.^[5]

Although the exact function is unknown in many tissues, podoplanin is generally receptive to detection via immunofluorescent staining and has been shown to co-localize with the protein nestin, a type VI intermediate filament protein expressed almost primarily in neural tissues.^[6] Currently, the only protein known to interact with podoplanin physiologically is CLEC-2, a C-type lectin 2 expressed on platelets and on hematopoietic cells.^[7] Both serve a role in the proper formation of blood/lymphatic connections in embryonic development.

Clinical significance

PDPN has been studied extensively in the cancer field. It is a specific lymphatic vessel marker, and since lymphangiogenesis levels are correlated with poor prognosis in cancer patients, it can be used as a diagnostic marker.^[4] It is often upregulated in certain types of cancer, including several types of squamous cell carcinomas, malignant mesothelioma and brain tumors.^[4] Moreover, it can be upregulated by cancer-associated fibroblasts (CAFs) in the tumor stroma,^{[4] [8]} where it has been associated with poor prognosis.^[9]

In squamous cell carcinomas, PDPN is believed to play a key role in the cancer cell invasiveness by controlling invadopodia, and thus mediating efficient ECM degradation.^[10]

Further reading

• Wicki A, Christofori G . The potential role of podoplanin in tumour invasion . British Journal of Cancer . 96 . 1 . 1–5 . January 2007 . 17179989 . 2360213 . 10.1038/sj.bjc.6603518 .
• Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC . Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening . Genomics . 23 . 1 . 42–50 . September 1994 . 7829101 . 10.1006/geno.1994.1457 .
• Cross SH, Charlton JA, Nan X, Bird AP . Purification of CpG islands using a methylated DNA binding column . Nature Genetics . 6 . 3 . 236–44 . March 1994 . 8012384 . 10.1038/ng0394-236 . 12847618 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Kato Y, Fujita N, Kunita A, Sato S, Kaneko M, Osawa M, Tsuruo T . Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors . The Journal of Biological Chemistry . 278 . 51 . 51599–605 . December 2003 . 14522983 . 10.1074/jbc.M309935200 . 11119751 . free .
• Kaneko M, Kato Y, Kunita A, Fujita N, Tsuruo T, Osawa M . Functional sialylated O-glycan to platelet aggregation on Aggrus (T1alpha/Podoplanin) molecules expressed in Chinese hamster ovary cells . The Journal of Biological Chemistry . 279 . 37 . 38838–43 . September 2004 . 15231832 . 10.1074/jbc.M407210200 . 37651644 . free .
• Martín-Villar E, Scholl FG, Gamallo C, Yurrita MM, Muñoz-Guerra M, Cruces J, Quintanilla M . Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas . International Journal of Cancer . 113 . 6 . 899–910 . March 2005 . 15515019 . 10.1002/ijc.20656 . 10261/81190 . 2895153 . free .
• Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M . Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors . The American Journal of Pathology . 166 . 3 . 913–21 . March 2005 . 15743802 . 1602360 . 10.1016/S0002-9440(10)62311-5 .
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Hultgård-Ekwall AK, Mayerl C, Rubin K, Wick G, Rask-Andersen H . An interstitial network of podoplanin-expressing cells in the human endolymphatic duct . Journal of the Association for Research in Otolaryngology . 7 . 1 . 38–47 . March 2006 . 16408168 . 2504586 . 10.1007/s10162-005-0021-8 .
• Dumoff KL, Chu CS, Harris EE, Holtz D, Xu X, Zhang PJ, Acs G . Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation . Modern Pathology . 19 . 5 . 708–16 . May 2006 . 16528371 . 10.1038/modpathol.3800580 . 502212 . free .
• Omachi T, Kawai Y, Mizuno R, Nomiyama T, Miyagawa S, Ohhashi T, Nakayama J . Immunohistochemical demonstration of proliferating lymphatic vessels in colorectal carcinoma and its clinicopathological significance . Cancer Letters . 246 . 1–2 . 167–72 . February 2007 . 16574316 . 10.1016/j.canlet.2006.02.013 .
• Mishima K, Kato Y, Kaneko MK, Nishikawa R, Hirose T, Matsutani M . Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression . Acta Neuropathologica . 111 . 5 . 483–8 . May 2006 . 16596424 . 10.1007/s00401-006-0063-y . 17760421 .
• Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G . Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton . Cancer Cell . 9 . 4 . 261–72 . April 2006 . 16616332 . 10.1016/j.ccr.2006.03.010 . free .
• Mishima K, Kato Y, Kaneko MK, Nakazawa Y, Kunita A, Fujita N, Tsuruo T, Nishikawa R, Hirose T, Matsutani M . Podoplanin expression in primary central nervous system germ cell tumors: a useful histological marker for the diagnosis of germinoma . Acta Neuropathologica . 111 . 6 . 563–8 . June 2006 . 16718353 . 10.1007/s00401-006-0033-4 . 25060022 .

Notes and References

1. Zimmer G, Oeffner F, Von Messling V, Tschernig T, Gröness HJ, Klenk HD, Herrler G . Cloning and characterization of gp36, a human mucin-type glycoprotein preferentially expressed in vascular endothelium . The Biochemical Journal . 341 (Pt 2) . Pt 2 . 277–84 . July 1999 . 10393083 . 1220357 . 10.1042/0264-6021:3410277 .
2. Ma T, Yang B, Matthay MA, Verkman AS . Evidence against a role of mouse, rat, and two cloned human t1alpha isoforms as a water channel or a regulator of aquaporin-type water channels . American Journal of Respiratory Cell and Molecular Biology . 19 . 1 . 143–9 . July 1998 . 9651190 . 10.1165/ajrcmb.19.1.2953 .
3. Web site: Entrez Gene: PDPN podoplanin.
4. Astarita JL, Acton SE, Turley SJ . Podoplanin: emerging functions in development, the immune system, and cancer . Frontiers in Immunology . 3 . 283 . 2012 . 22988448 . 3439854 . 10.3389/fimmu.2012.00283 . free .
5. Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L . Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice . The Journal of Clinical Investigation . 118 . 11 . 3725–37 . November 2008 . 18924607 . 2567837 . 10.1172/JCI36077 .
6. Imaizumi Y, Amano I, Tsuruga E, Kojima H, Sawa Y . Immunohistochemical examination for the distribution of podoplanin-expressing cells in developing mouse molar tooth germs . Acta Histochemica et Cytochemica . 43 . 5 . 115–21 . October 2010 . 21060740 . 2965832 . 10.1267/ahc.10023 .
7. Herzog BH, Fu J, Wilson SJ, Hess PR, Sen A, McDaniel JM, Pan Y, Sheng M, Yago T, Silasi-Mansat R, McGee S, May F, Nieswandt B, Morris AJ, Lupu F, Coughlin SR, McEver RP, Chen H, Kahn ML, Xia L . Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 . Nature . 502 . 7469 . 105–9 . October 2013 . 23995678 . 3791160 . 10.1038/nature12501 . 2013Natur.502..105H .
8. Kitano H, Kageyama S, Hewitt SM, Hayashi R, Doki Y, Ozaki Y, Fujino S, Takikita M, Kubo H, Fukuoka J . Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival . Archives of Pathology & Laboratory Medicine . 134 . 10 . 1520–7 . October 2010 . 20923309 . 10.5858/2009-0114-OA.1 . 7556323 .
9. Chuang WY, Yeh CJ, Chao YK, Liu YH, Chang YS, Tseng CK, Chang HK, Wan YL, Hsueh C . Concordant podoplanin expression in cancer-associated fibroblasts and tumor cells is an adverse prognostic factor in esophageal squamous cell carcinoma . International Journal of Clinical and Experimental Pathology . 7 . 8 . 4847–56 . 2014 . 25197355 . 4152045 .
10. Martín-Villar E, Borda-d'Agua B, Carrasco-Ramirez P, Renart J, Parsons M, Quintanilla M, Jones GE . Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability . Oncogene . 34 . 34 . 4531–44 . August 2015 . 25486435 . 4430312 . 10.1038/onc.2014.388 .