Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition

The potential role of podoplanin in tumour invasion

“…In MCF7 cells, which express a high level of RhoA, podoplanin was found to downregulate RhoA activity, whereas in MDCK cells, which exhibit a low intrinsic activity of RhoA, its acitivity was enhanced by podoplanin. The basis for this unexpected finding is not clear, although it might reflect a different organisation of the cytoskeleton in different cell types (Martin-Villar et al, 2006). In both cases, inhibition of RhoA modulation led to reduced cell motility, strengthening the notion that the regulation of RhoA activity is causally involved in the pro-migratory phenotype observed in podoplanin-expressing cancer cells (Martin-Villar et al, 2006;Wicki et al, 2006).…”

“…These in vitro data support the concept that podoplanin expression in human cancers promotes migration and invasion of cancer cells in the absence of a cadherin switch and EMT. However, a recent report with MDCK cells demonstrates that the expression of podoplanin leads to increased single cell migration after loss of E-cadherin expression (Martin-Villar et al, 2006). We therefore must postulate that podoplanin is capable of inducing invasion in both settings, collective and single cell migration.…”

“…Indeed, podoplanin physically associates with ezrin (Scholl et al, 1999). In addition, overexpression of podoplanin in MCF7 cells, MDCK cells and HaCaT keratinocytes leads to a marked increase in phosphorylation of ezrin and other ERM proteins without affecting ezrin or moesin protein levels (Martin-Villar et al, 2006;Wicki et al, 2006). Thus, ERM-protein phosphorylation may link podoplanin expression to the observed rearrangement of the actin cytoskeleton.…”

Podoplanin deficient mice show a rhoa‐related hypoplasia of the sinus venosus myocardium including the sinoatrial node

“…ERM proteins bind to the podoplanin ERMbinding site to activate RhoA, a member of the Rho GTPase protein family controlling a wide variety of cellular processes including proliferation, differentiation, cell morphology and motility (Hall, 1994;Van and SouzaSchorey, 1997). The increased RhoA activity leads to "podoplanin-induced" EMT (Martin-Villar et al, 2006). With regard to this mechanism, lack of podoplanin has resulted in diminished expression of RhoA protein which may prevent the "podoplanin-induced" EMT with subsequent myocardial abnormalities of the venous pole.…”

“…Podoplanin can, therefore, be considered as an inhibitor of E-cadherin stimulating EMT. In addition, RhoA activation by podoplanin and ezrin interaction have been described to lead into podoplanin-induced EMT (Martin-Villar et al, 2006). Similar to E-cadherin, lack of podoplanin might lead to down-regulated RhoA and altered EMT.…”