Podoplanin: emerging functions in development, the immune system, and cancer

Abstract

Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer.

Keywords: CLEC-2; cancer-associated fibroblasts; lymph node stromal cells; lymphatic endothelial cells; platelets; podoplanin.

FIGURE 1

Molecular interactions of PDPN. PDPN interacts with a variety of intracellular and transmembrane proteins to mediate effects on cell migration and adhesion. The binding of PDPN to CD44 or ERMs results in increased cell migration and rearrangement of the actin cytoskeleton to generate actin-rich protrusions of the membrane. The three amino acids colored in pink (K, K, R) are the basic residues requires for ERM protein binding. Interactions between PDPN and CD9 affect metastasis and platelet aggregation. The engagement of PDPN by CLEC-2 causes increased motility in DCs and aggregation and activation of platelets. PDPN binds with high affinity to the chemokine CCL21 and while the consequences of this effect have not been examined, it may play a role in facilitating leukocyte migration. Finally, PDPN binding to galectin-8 may modulate adhesion of LECs.

FIGURE 2

Transcriptional regulation of PDPN expression. PDPN expression can be upregulated by a number of pro-inflammatory cytokines, including IL-22, IL-6, IFN-γ, TGF-β, IL-1β, and TNF-α, but the signaling pathways involved are largely unknown. PDPN upregulation induced by TGF-β requires Smad2/3 and 4 activity, while upregulation induced by IFN-ψ depends on STAT1 and STAT3 and that of IL-6 and IL-22 depends on STAT3. The PI3K-AKT-AP-1 pathway can also induce PDPN expression in brain tumors that have lost the negative regulation normally provided by PTEN. AP-1, a transcription factor comprised of Fos and Jun proteins, binds to the tetradecanoylphorbol acetate-responsive element (TRE) in the promoter of PDPN, which is heavily methylated.