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Frontiers of Medicine

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Front. Med.    2015, Vol. 9 Issue (4) : 421-430    https://doi.org/10.1007/s11684-015-0424-9
REVIEW
Emerging roles of podoplanin in vascular development and homeostasis
Yanfang Pan1,2,*(),Lijun Xia3
1. Department of Non-Communicable Diseases Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
2. State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
3. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, OK 73104, USA
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Abstract

Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymph nodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Prox1 and modification of PDPN with core 1-derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function.
Keywords podoplanin      CLEC-2      Prox1      O-glycosylation      lymphatic vascular development and maintenance      lymphoid organ homeostasis     
Corresponding Author(s): Yanfang Pan   
Just Accepted Date: 23 September 2015   Online First Date: 26 October 2015    Issue Date: 26 November 2015
 Cite this article:   
Yanfang Pan,Lijun Xia. Emerging roles of podoplanin in vascular development and homeostasis[J]. Front. Med., 2015, 9(4): 421-430.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0424-9
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I4/421
Fig.1  Steps of mouse lymphangiogenesis. At E8.5, cardinal vein endothelial cells (ECs) become lymphatic competent. At E9−E9.5, a subset of cardinal vein ECs begins expressing Sox18 and subsequently, Prox1 at E9.75. Starting at E10.5, PDPN is expressed in ECs. At E11.5, primary lymph sac is formed from sprouted LECs, with aggregate platelets to seal and separate from the vein. Mature lymphatic vessels are then developed from the primary lymph sac. Prox1 and possibly PDPN are critical not only for separating blood and lymphatic vascular system, but also for maintaining LEC identity.
Fig.2  Mechanism of blood and lymphatic vessel separation. PDPN is O-glycosylated during biosynthesis in LECs. Cell surface-exposed PDPN binds to platelet receptor CLEC-2 and activates the Syk tyrosine kinase and SLP-76 adaptor protein. Syk/SLP-76 signaling leads to downstream activation of phospholipase C-γ2 (PLC-γ2), resulting in platelet activation. Aggregated platelets form a plug to seal off the growing primary lymph sac from the cardinal vein.
Fig.3  PDPN is a mucin-type O-glycoprotein. (A) Comparison of PDPN sequences of three species. Signal sequence is underlined in blue. Sites for potential O-glycosylation (boxed in red), transmembrane domain (underlined in green), and cytoplasmic domain (underlined in red) are highly conserved across species. (B) Biosynthesis of mucin-type O-glycans. Arrow-heads indicate possible branching, elongation, sialylation, and fucosylation.
Fig.4  Schematic cartoon of PDPN. Signal peptide amino acid is shown in gray. Potential O-glycosylation sites (serine or threonine) are shown in blue, with core 1 O-glycans attached. Only one potential N-glycosylation site is shown in green (asparagine 60). Platelet aggregation-stimulating domains are underlined in red.
Fig.5  Regulation of PDPN expression in LECs. At the transcriptional stage, Prox1 serves as a master regulator of LEC identity. Prox1 binds to the 5′ regulatory sequence of Pdpn (with or without co-factors) and induces PDPN expression. At the translational level, PDPN is synthesized and modified by C1galt1 to attach core 1 O-glycans to the protein backbone. The normally glycosylated PDPN is presented on the surface of LECs and able to interact with CLEC-2 on the platelet surface. Platelets are then activated through the Syk/SLP-76 signaling pathway and finally form aggregates. When C1galt1 is deficient, newly synthesized PDPN is not protected by core 1 O-glycans and is easily degraded by lymph metalloproteinases and/or other proteases.
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