PDPN
Podoplanin is a protein that in humans is encoded by the PDPN gene.[5][6][7]
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.[8]
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.[7]
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.[9]
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.[9]
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.[10] 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.[11] 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.[8] It is often upregulated in certain types of cancer, including several types of squamous cell carcinomas, malignant mesothelioma and brain tumors.[8] Moreover, it can be upregulated by cancer-associated fibroblasts (CAFs) in the tumor stroma,[8][12] where it has been associated with poor prognosis.[13]
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.[14]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000162493 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028583 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Zimmer G, Oeffner F, Von Messling V, Tschernig T, Gröness HJ, Klenk HD, Herrler G (July 1999). "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. doi:10.1042/0264-6021:3410277. PMC 1220357. PMID 10393083.
- ^ Ma T, Yang B, Matthay MA, Verkman AS (July 1998). "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. doi:10.1165/ajrcmb.19.1.2953. PMID 9651190.
- ^ a b "Entrez Gene: PDPN podoplanin".
- ^ a b c d Astarita JL, Acton SE, Turley SJ (2012). "Podoplanin: emerging functions in development, the immune system, and cancer". Frontiers in Immunology. 3: 283. doi:10.3389/fimmu.2012.00283. PMC 3439854. PMID 22988448.
- ^ a b 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 (November 2008). "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. doi:10.1172/JCI36077. PMC 2567837. PMID 18924607.
- ^ Imaizumi Y, Amano I, Tsuruga E, Kojima H, Sawa Y (October 2010). "Immunohistochemical examination for the distribution of podoplanin-expressing cells in developing mouse molar tooth germs". Acta Histochemica et Cytochemica. 43 (5): 115–21. doi:10.1267/ahc.10023. PMC 2965832. PMID 21060740.
- ^ 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 (October 2013). "Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2". Nature. 502 (7469): 105–9. Bibcode:2013Natur.502..105H. doi:10.1038/nature12501. PMC 3791160. PMID 23995678.
- ^ Kitano H, Kageyama S, Hewitt SM, Hayashi R, Doki Y, Ozaki Y, Fujino S, Takikita M, Kubo H, Fukuoka J (October 2010). "Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival". Archives of Pathology & Laboratory Medicine. 134 (10): 1520–7. doi:10.5858/2009-0114-OA.1. PMC 7556323. PMID 20923309.
- ^ Chuang WY, Yeh CJ, Chao YK, Liu YH, Chang YS, Tseng CK, Chang HK, Wan YL, Hsueh C (2014). "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. PMC 4152045. PMID 25197355.
- ^ Martín-Villar E, Borda-d'Agua B, Carrasco-Ramirez P, Renart J, Parsons M, Quintanilla M, Jones GE (August 2015). "Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability". Oncogene. 34 (34): 4531–44. doi:10.1038/onc.2014.388. PMC 4430312. PMID 25486435.
Further reading
- Wicki A, Christofori G (January 2007). "The potential role of podoplanin in tumour invasion". British Journal of Cancer. 96 (1): 1–5. doi:10.1038/sj.bjc.6603518. PMC 2360213. PMID 17179989.
- Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC (September 1994). "Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening". Genomics. 23 (1): 42–50. doi:10.1006/geno.1994.1457. PMID 7829101.
- Cross SH, Charlton JA, Nan X, Bird AP (March 1994). "Purification of CpG islands using a methylated DNA binding column". Nature Genetics. 6 (3): 236–44. doi:10.1038/ng0394-236. PMID 8012384. S2CID 12847618.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Kato Y, Fujita N, Kunita A, Sato S, Kaneko M, Osawa M, Tsuruo T (December 2003). "Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors". The Journal of Biological Chemistry. 278 (51): 51599–605. doi:10.1074/jbc.M309935200. PMID 14522983. S2CID 11119751.
- Kaneko M, Kato Y, Kunita A, Fujita N, Tsuruo T, Osawa M (September 2004). "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. doi:10.1074/jbc.M407210200. PMID 15231832. S2CID 37651644.
- Martín-Villar E, Scholl FG, Gamallo C, Yurrita MM, Muñoz-Guerra M, Cruces J, Quintanilla M (March 2005). "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. doi:10.1002/ijc.20656. hdl:10261/81190. PMID 15515019. S2CID 2895153.
- Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M (March 2005). "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. doi:10.1016/S0002-9440(10)62311-5. PMC 1602360. PMID 15743802.
- 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 (2007). "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. doi:10.1093/dnares/12.2.117. PMID 16303743.
- Hultgård-Ekwall AK, Mayerl C, Rubin K, Wick G, Rask-Andersen H (March 2006). "An interstitial network of podoplanin-expressing cells in the human endolymphatic duct". Journal of the Association for Research in Otolaryngology. 7 (1): 38–47. doi:10.1007/s10162-005-0021-8. PMC 2504586. PMID 16408168.
- Dumoff KL, Chu CS, Harris EE, Holtz D, Xu X, Zhang PJ, Acs G (May 2006). "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. doi:10.1038/modpathol.3800580. PMID 16528371. S2CID 502212.
- Omachi T, Kawai Y, Mizuno R, Nomiyama T, Miyagawa S, Ohhashi T, Nakayama J (February 2007). "Immunohistochemical demonstration of proliferating lymphatic vessels in colorectal carcinoma and its clinicopathological significance". Cancer Letters. 246 (1–2): 167–72. doi:10.1016/j.canlet.2006.02.013. PMID 16574316.
- Mishima K, Kato Y, Kaneko MK, Nishikawa R, Hirose T, Matsutani M (May 2006). "Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression". Acta Neuropathologica. 111 (5): 483–8. doi:10.1007/s00401-006-0063-y. PMID 16596424. S2CID 17760421.
- Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G (April 2006). "Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton". Cancer Cell. 9 (4): 261–72. doi:10.1016/j.ccr.2006.03.010. PMID 16616332.
- Mishima K, Kato Y, Kaneko MK, Nakazawa Y, Kunita A, Fujita N, Tsuruo T, Nishikawa R, Hirose T, Matsutani M (June 2006). "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. doi:10.1007/s00401-006-0033-4. PMID 16718353. S2CID 25060022.