Podoplanin associates with CD44 to promote directional cell migration.
Podoplanin is a transmembrane glycoprotein up-regulated in different human tumors, especially those derived from squamous stratified epithelia (SCCs). Its expression in tumor cells is linked to increased cell migration and invasiveness; however, the mechanisms underlying this process remain poorly understood. Here we report that CD44, the major hyaluronan (HA) receptor, is a novel partner for podoplanin. Expression of the CD44 standard isoform (CD44s) is coordinately up-regulated together with that of podoplanin during progression to highly aggressive SCCs in a mouse skin model of carcinogenesis, and during epithelial-mesenchymal transition (EMT). In carcinoma cells, CD44 and podoplanin colocalize at cell surface protrusions. Moreover, CD44 recruitment promoted by HA-coated beads or cross-linking with a specific CD44 antibody induced corecruitment of podoplanin. Podoplanin-CD44s interaction was demonstrated both by coimmunoprecipitation experiments and, in vivo, by fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy (FRET/FLIM), the later confirming its association on the plasma membrane of cells with a migratory phenotype. Importantly, we also show that podoplanin promotes directional persistence of motility in epithelial cells, a feature that requires CD44, and that both molecules cooperate to promote directional migration in SCC cells. Our results support a role for CD44-podoplanin interaction in driving tumor cell migration during malignancy.
Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, SE1UL, UK. ester.martin@kcl.ac.uk
Ester
E
Martín-Villar
Beatriz
B
Fernández-Muñoz
Maddy
M
Parsons
Maria M
MM
Yurrita
Diego
D
Megías
Eduardo
E
Pérez-Gómez
Gareth E
GE
Jones
Miguel
M
Quintanilla
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology*; D015854:Up-Regulation; D000098853:Podoplanin
D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; C117468:PDPN protein, human; D000098853:Podoplanin