Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity

Bianchi, Roberta; Fischer, Eliane; Yuen, Don; Ernst, Ellen; Ochsenbein, Alexandra M.; Chen, Lu; Otto, Vivianne I.; Detmar, Michael

doi:10.1074/jbc.m114.550525

Cited by 9 publications

(11 citation statements)

References 40 publications

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“…These acidic residues interact with a series of Arg residues in CLEC-2. These data are consistent with the results of Bianchi et al (2014), which showed that in mouse podoplanin, O-glycosylation of Thr-34 (localized in PLAG1…”

supporting

confidence: 82%

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

Renart

Carrasco-Ramírez

Fernández‐Muñoz³

et al. 2015

International Review of Cell and Molecular Biology

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supporting

confidence: 82%

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

Renart

Carrasco-Ramírez

Fernández‐Muñoz³

et al. 2015

International Review of Cell and Molecular Biology

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“…20 In addition, blocking of podoplanin function by administration of podoplanin-Fc during late embryonic development resulted in a less complex diaphragmatic lymphatic network in pups. 41 Thus, it is likely that, early in development, podoplanin functionally contributes not only to the separation of the blood vascular and the lymphatic system but also to LV patterning. However, our data indicate that after birth, podoplanin is dispensable for proper LV maintenance and drainage function.…”

Section: Discussionmentioning

confidence: 99%

Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes

Bianchi

Russo

Bachmann

et al. 2017

ATVB

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Objective-The lymphatic vascular system exerts major physiological functions in the transport of interstitial fluid from peripheral tissues back to the blood circulation and in the trafficking of immune cells to lymph nodes. Previous studies in global constitutive knockout mice for the lymphatic transmembrane molecule podoplanin reported perinatal lethality and a complex phenotype with lung abnormalities, cardiac defects, lymphedema, blood-filled lymphatic vessels, and lack of lymph node organization, reflecting the importance of podoplanin expression not only by the lymphatic endothelium but also by a variety of nonendothelial cell types. Therefore, we aimed to dissect the specific role of podoplanin expressed by adult lymphatic vessels. Approach and Results-We generated an inducible, lymphatic-specific podoplanin knockout mouse model (Pdpn ΔLEC) and induced gene deletion postnatally. Pdpn ΔLEC mice were viable, and their lymphatic vessels appeared morphologically normal with unaltered fluid drainage function. Intriguingly, Pdpn ΔLEC mice had blood-filled lymph nodes and vessels, most frequently in the neck and axillary region, and displayed a blood-filled thoracic duct, suggestive of retrograde filling of blood from the blood circulation into the lymphatic system. Histological and fluorescence-activated cell sorter analyses revealed normal lymph node organization with the presence of erythrocytes within lymph node lymphatic vessels but not surrounding high endothelial venules. Moreover, fluorescein isothiocyanate painting experiments revealed reduced dendritic cell migration to lymph nodes in Pdpn ΔLEC mice. Conclusions-These

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“…The transgenic overexpression of soluble PDPN-Fc in mouse skin provoked platelet activation via CLEC-2, causing disseminated intravascular coagulation and thrombocytopenia [121]. This event required O -glycosylated T34, as mutation of this residue, considered to be essential for the binding of podoplanin to CLEC-2, reduced platelet activation and its side effects [122]. However, the mutant soluble PDPN-Fc retained the ability to inhibit lymphangiogenesis in vitro and in vivo [122], suggesting that the function of podoplanin in LECs is independent of binding to CLEC-2.…”

Section: Podoplanin In Inflammatory Lymphangiogenesismentioning

confidence: 99%

“…This event required O -glycosylated T34, as mutation of this residue, considered to be essential for the binding of podoplanin to CLEC-2, reduced platelet activation and its side effects [122]. However, the mutant soluble PDPN-Fc retained the ability to inhibit lymphangiogenesis in vitro and in vivo [122], suggesting that the function of podoplanin in LECs is independent of binding to CLEC-2. The above conclusion is contradictory with earlier reports showing that platelets inhibit lymphangiogenesis [58,123].…”

Section: Podoplanin In Inflammatory Lymphangiogenesismentioning

confidence: 99%

Podoplanin in Inflammation and Cancer

Quintanilla

Montero-Montero

Renart

et al. 2019

IJMS

179

182

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Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.

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Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity

Cited by 9 publications

References 40 publications

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes

Podoplanin in Inflammation and Cancer

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