Abstract
Podoplanin is a small membrane mucin expressed in tumors associated with malignant progression. It is enriched at cell-surface protrusions where it colocalizes with members of the ERM (ezrin, radixin, moesin) protein family. Here, we found that human podoplanin directly interacts with ezrin (and moesin) in vitro and in vivo through a cluster of basic amino acids within its cytoplasmic tail, mainly through a juxtamembrane dipeptide RK. Podoplanin induced an epithelial-mesenchymal transition in MDCK cells linked to the activation of RhoA and increased cell migration and invasiveness. Fluorescence time-lapse video observations in migrating cells indicate that podoplanin might be involved in ruffling activity as well as in retractive processes. By using mutant podoplanin constructs fused to green fluorescent protein we show that association of the cytoplasmic tail with ERM proteins is required for upregulation of RhoA activity and epithelial-mesenchymal transition. Furthermore, expression of either a dominant-negative truncated variant of ezrin or a dominant-negative mutant form of RhoA blocked podoplanin-induced RhoA activation and epithelial-mesenchymal transition. These results provide a mechanistic basis to understand the role of podoplanin in cell migration or invasiveness.
Highlights
Epithelial to mesenchymal transition (EMT) represents a phenotypic conversion by which epithelial cells lose their polarity and cohesiveness and acquire migratory features characteristic of fibroblasts
We reported that podoplanin, a small mucinlike transmembrane glycoprotein known as PA2.26 antigen or T1␣ among other names, induced the conversion from an epithelial to a fibroblast-like morphology when ectopically expressed in keratinocytes (Scholl et al, 1999)
We show that wild-type human podoplanin promotes a complete EMT in Madin-Darby canine kidney (MDCK) type-II epithelial cells, a well-characterized cellular model to analyze the molecular mechanisms of epithelial cell plasticity (Gotzmann et al, 2004)
Summary
Epithelial to mesenchymal transition (EMT) represents a phenotypic conversion by which epithelial cells lose their polarity and cohesiveness and acquire migratory features characteristic of fibroblasts. Podoplanin is expressed in a variety of normal cells and tissues, including mesothelia, certain types of epithelia, neuronal cells, osteocytes and endothelia of lymphatic capillaries (Rishi et al, 1995; Wetterwald et al, 1996; Williams et al, 1996; Scholl et al, 1999; Kotani et al, 2003; Schacht et al, 2005; Breiteneder-Geleff et al, 1997; Breiteneder-Geleff et al, 1999). The podoplanin null mice show defects in the lymphatic pattern formation associated with congenital lymphedema, dilation of vessels and diminished lymphatic transport (Schacht et al, 2003). These data point to an important role for podoplanin in the development of the lung and lymphatic vascular system, but its precise biological function remains poorly understood
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