Podoplanin (Pdpn) is a type 1 transmembrane mucin-type O-glycoprotein [1, 2]. It consists of 172 amino acids in mice and 163 amino acids in humans. It is expressed in lymphafic endothelial cells (LECs) as well as many other cell types including alveolar type I epithelial cells, podocytes, osteoblast cells, and several tumor cell types [1-4]. Hence, it is also known as Tia, OTS-8, gp36 and Aggrus, based on the cell type in which it has been identified [2, 5-8]. Pdpn has an extracellular domain, a single transmembrane domain, and a short cytoplasmic tail (Fig. 1 A). It is highly consen/ed between rodents and humans (Fig. 1 A). Protein homology is particulariy evident in the cytoplasmic carboxy-terminal tail of Pdpn, suggesfing important functions. Indeed, the cytoplasmic domain of Pdpn has been shown to interact with members ofthe ERM (ezrin, radixin, moesin) proteins in epithelial cells, and to subsequently activate RhoA and promote cell transdifferentiation [9]. A striking feature of the extracellular domain of Pdpn is a high content of serine and threonine residues that could potenfially be O-glycosylated [10,11] (Fig. IA). Mucin-type O-glycosylation is a prevalent form of post-translational modification of membrane and secreted proteins [12-15]. It occurs in the Golgi apparatus via sequential reactions catalyzed by specific glycosyltransferases (Fig. IB). The core of all mucin-type O-glycans is serine/threonine-linked Nacetylgalactosamine (GalNAcal-Ser/Thr), also known as Tn antigen, which is normally further modified to form distinct subtypes of Oglycans. Among them, core 1 O-glycans are a predominant form. Core 1 O-glycans are synthesized by adding galactose (Gal) to Tn antigen, a reaction catalyzed solely by the T-synthase (core 1 synthase, Cigaltl) [13-16). Core 1 structure can be further branched to form extended core 1, core 2 structures, or can be modified by adding sialic acids. These glycans are known as core 1-derived O-glycans [15,16]. Core 1-derived O-glycans are present in most cell types, especially in epithelial cells and endothelial cells [15]. Altered O-glycosylafion can affect numerous processes such as glycoprotein conformafion, trafficking, sorting, or degradafion [14,17,18]. Moreover, the O-glycosylafion state of glycoproteins may also dictate changes in cell-cell interacfions and/or cell signaling [19]. The extracellular domain of mouse Pdpn contains 24 potential sites of O-glycosylafion (Fig. 1A). The molecular weight of core Pdpn protein is about 17 kDa, however, Pdpn isolated from different tissues has molecular weight ranging from 37 to 41 kDa, suggesting extensive O-glycosylafion. Our recent study provides the first evidence in vivo that O-glycosylation is essential for fhe cell surface expression of Pdpn [14], although how O-glycosylafion regulates Pdpn expression/funcfion remains to be determined. Our study also revealed a critical contribution of core 1-derived O-glycans and Pdpn to lymphatic vascular development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL085607-06
Application #
8112972
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2011
Total Cost
$482,413
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Mehta-D'souza, Padmaja; Klopocki, Arkadiusz G; Oganesyan, Vaheh et al. (2017) Glycan Bound to the Selectin Low Affinity State Engages Glu-88 to Stabilize the High Affinity State under Force. J Biol Chem 292:2510-2518
Panicker, Sumith R; Mehta-D'souza, Padmaja; Zhang, Nan et al. (2017) Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice. Blood 130:181-191
Liu, Zhenghui; Yago, Tadayuki; Zhang, Nan et al. (2017) L-selectin mechanochemistry restricts neutrophil priming in vivo. Nat Commun 8:15196
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Rahman, H N Ashiqur; Wu, Hao; Dong, Yunzhou et al. (2016) Selective Targeting of a Novel Epsin-VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis. Circ Res 118:957-969
Liu, Zhenghui; Zhang, Nan; Shao, Bojing et al. (2016) Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. J Biol Chem 291:1441-7
Brazil, Jennifer C; Sumagin, Ronen; Cummings, Richard D et al. (2016) Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. Am J Pathol 186:297-311
Chen, Wei-Sheng; Cao, Zhiyi; Sugaya, Satoshi et al. (2016) Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat Commun 7:11302
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2016) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 126:1607
Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126:2254-66

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