title: Serines in the intracellular tail of podoplanin (PDPN) regulate cell motility.
abstract: Podoplanin (PDPN) is a transmembrane receptor that affects the activities of Rho, ezrin, and other proteins to promote tumor cell motility, invasion, and metastasis. PDPN is found in many types of cancer and may serve as a tumor biomarker and chemotherapeutic target. The intracellular region of PDPN contains only two serines, and these are conserved in mammals including mice and humans. We generated cells from the embryos of homozygous null Pdpn knock-out mice to investigate the relevance of these serines to cell growth and migration on a clear (PDPN-free) background. We report here that one or both of these serines can be phosphorylated by PKA (protein kinase A). We also report that conversion of these serines to nonphosphorylatable alanine residues enhances cell migration, whereas their conversion to phosphomimetic aspartate residues decreases cell migration. These results indicate that PKA can phosphorylate PDPN to decrease cell migration. In addition, we report that PDPN expression in fibroblasts causes them to facilitate the motility and viability of neighboring melanoma cells in coculture. These findings shed new light on how PDPN promotes cell motility, its role in tumorigenesis, and its utility as a functionally relevant biomarker and chemotherapeutic target.
authors.affiliation: Graduate School of Biomedical Sciences and Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Krishnan
authors.forename: Jhon A
authors.initials: JA
authors.lastname: Ochoa-Alvarez
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Shen
authors.forename: Evan
authors.initials: E
authors.lastname: Nevel
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Lakshminarayanan
authors.forename: Mary C
authors.initials: MC
authors.lastname: Williams
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ramirez
authors.forename: W Todd
authors.initials: WT
authors.lastname: Miller
authors.forename: Gary S
authors.initials: GS
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012694:Serine; C490441:Pdpn protein, mouse; D000098853:Podoplanin