Furthermore, overexpression of CD44 can attenuate PDPN-driven actomyosin contractility. Interestingly, Pdpn and Cd44 mRNA expression are also coregulated, and knockdown of Cd44 results in lower expression levels of PDPN. PDPN and CD44 interactions are mediated through their transmembrane domains and are also dependent on cholesterol levels in the plasma membrane. We have recently reported that CD44, a non-kinase transmembrane glycoprotein and receptor for hyaluronic acid, is a key PDPN binding partner required for the response of FRCs to CLEC-2 + dendritic cells. The transmembrane domain of PDPN may in fact be a key regulator of PDPN function, allowing PDPN molecules to rearrange within different regions of the plasma membrane and to permit the interactions between PDPN and other membrane binding partners. It has been reported that PDPN can directly bind to ERM proteins (ezrin, radixin and moesin) to regulate RhoA GTPase and actomyosin contractility. Therefore, it has been difficult to determine how PDPN is required for so many diverse functions in such a range of cell types and tissue contexts. It is known that PDPN has only a very short cytoplasmic tail of just 10 amino acids. The same interaction with platelets also plays an important role in the function of high endothelial venues (HEVs) in lymph nodes, acting to prevent blood from leaking into the tissues. PDPN can also interact with platelets through CLEC-2 which is a required interaction for the physiological separation of blood and lymphatic vasculature during development. For example, in non-motile tissue structures, such as FRCs in lymph nodes and on lymphatic endothelial cells, PDPN can act as a ligand to promote the migration of dendritic cells along stromal cell scaffolds through the direct binding of the C-type lectin-like receptor CLEC-2. PDPN overexpression has been linked to cell migration, cell adhesion and cytoskeletal contractility in cancer cells. PDPN overexpression has also been noted in inflammatory diseases, tissue damage and a wide range of cancers, and is directly correlated with disease outcomes, but the downstream signalling pathways and mechanisms of action of PDPN are still not fully understood. Podoplanin (PDPN) has been determined as a mechanical sensor in FRCs, and mice with conditional genetic deletion of PDPN in fibroblastic stroma, Pdgfra Δ Pdpn mice, exhibit attenuated lymph node expansion and altered immune activation. Further, the fibroblastic reticular network is the key mechanically sensitive component of the lymph node capable of determining the physical properties of the tissue in steady state and adapting to permit lymph node expansion. Lymph node tissue architecture is determined by stromal cell structures fibroblastic reticular cells (FRCs) that establish cellular networks linking lymph and blood vasculature which provide trafficking routes for lymphocytes and myeloid cells and generate growth factor and survival factors for the immune cell populations they support. Lymph nodes are highly organized tissues that contain and compartmentalize immune cell types to orchestrate adaptive immune responses. These results suggest that CD44 expression is required to stabilize large pools of PDPN at the membrane of FRCs upon CLEC-2 interaction, revealing the molecular mechanism through which CD44 facilitates cellular crosstalk between FRCs and DCs. more than 12 proteins per cluster) in a CD44-dependent manner. Our results indicate that CLEC-2 interaction leads to the formation of large PDPN clusters (i.e. Here, we use DNA-PAINT, a quantitative single molecule super-resolution technique, to visualize and quantify how PDPN clustering is regulated in the plasma membrane of FRCs. The hyaluronic acid receptor CD44 is known to be required for FRCs to respond to DCs but the mechanism of action is not fully elucidated. CLEC-2 binds to the membrane glycoprotein podoplanin (PDPN) on FRCs, inhibiting actomyosin contractility through the FRC network and permitting lymph node expansion. Upon initial immune challenge, dendritic cells (DCs) migrate to lymph nodes and interact with fibroblastic reticular cells (FRCs) via C-type lectin-like receptor 2 (CLEC-2).
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