title: PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility.
abstract: Podoplanin (PDPN) is a transmembrane glycoprotein that promotes tumor cell migration, invasion, and cancer metastasis. In fact, PDPN expression is induced in many types of cancer. Thus, PDPN has emerged as a functionally relevant cancer biomarker and chemotherapeutic target. PDPN contains 2 intracellular serine residues that are conserved between species ranging from mouse to humans. Recent studies indicate that protein kinase A (PKA) can phosphorylate PDPN in order to inhibit cell migration. However, the number and identification of specific residues phosphorylated by PKA have not been defined. In addition, roles of other kinases that may phosphorylate PDPN to control cell migration have not been investigated. We report here that cyclin dependent kinase 5 (CDK5) can phosphorylate PDPN in addition to PKA. Moreover, results from this study indicate that PKA and CDK5 cooperate to phosphorylate PDPN on both intracellular serine residues to decrease cell motility. These results provide new insight into PDPN phosphorylation dynamics and the role of PDPN in cell motility. Understanding novel mechanisms of PDPN intracellular signaling could assist with designing novel targeted chemotherapeutic agents and procedures.
authors.affiliation: Graduate School of Biomedical Sciences and Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Science Center, 2 Medical Center Drive, Stratford, NJ 08084, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Krishnan
authors.affiliation: Graduate School of Biomedical Sciences and Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Science Center, 2 Medical Center Drive, Stratford, NJ 08084, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Retzbach
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Ramirez
authors.affiliation: Center for Advanced Proteomics Research and Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School Cancer Center,205 S. Orange Avenue, F-1226, Newark, NJ 07103, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Advanced Proteomics Research and Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School Cancer Center,205 S. Orange Avenue, F-1226, Newark, NJ 07103, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Basic Science Tower T-5, Stony Brook University, Stony Brook, NY 11794-8661, USA.
authors.forename: W Todd
authors.initials: WT
authors.lastname: Miller
authors.affiliation: Graduate School of Biomedical Sciences and Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Science Center, 2 Medical Center Drive, Stratford, NJ 08084, USA. Electronic address: gary.goldberg@rowan.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D051360:Cyclin-Dependent Kinase 5; D008562:Membrane Glycoproteins; D012694:Serine; C490441:Pdpn protein, mouse; D000098853:Podoplanin
keywords: Cell migration; Cyclin dependent Kinase 5; Podoplanin; Protein Kinase A; Serine phosphorylation