title: Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway.
abstract: Cyclophilin A (CypA) is overexpressed in a number of human cancer types, but the mechanisms by which the protein promotes oncogenic properties of cells are not understood. Here we demonstrate that CypA binds the CrkII adaptor protein and prevents it from switching to the inhibited state. CrkII influences cell motility and invasion by mediating signaling through its SH2 and SH3 domains. CrkII Tyr221 phosphorylation by the Abl or EGFR kinases induces an inhibited state of CrkII by means of an intramolecular SH2-pTyr221 interaction, causing signaling interruption. We show that the CrkII phosphorylation site constitutes a binding site for CypA. Recruitment of CypA sterically restricts the accessibility of Tyr221 to kinases, thereby suppressing CrkII phosphorylation and promoting the active state. Structural, biophysical and in vivo data show that CypA augments CrkII-mediated signaling. A strong stimulation of cell migration is observed in cancer cells wherein both CypA and CrkII are greatly upregulated.
authors.affiliation: Department of Biochemistry, Molecular Biology &Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.|Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Tamjeed
authors.initials: T
authors.lastname: Saleh
authors.affiliation: Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jankowski
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Sriram
authors.affiliation: Department of Biochemistry, Molecular Biology &Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.|Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Shreyas
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Ki-Bum
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA.
authors.forename: Lissette Alicia
authors.initials: LA
authors.lastname: Cruz
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA.
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Rodriguez
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Birge
authors.affiliation: Department of Biochemistry, Molecular Biology &Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.|Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA.|Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Kalodimos
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D002151:Calorimetry; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D021984:Cyclophilin A / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016374:Oncogene Proteins v-abl; D050737:Proto-Oncogene Proteins c-crk; D021984:Cyclophilin A