PTK7 is a positive allosteric modulator of GPR133 signaling in glioblastoma
Joshua D. Frenster,
Hediye Erdjument-Bromage,
Gabriele Stephan,
Niklas Ravn-Boess,
Shuai Wang,
Wenke Liu,
Devin Bready,
Jordan Wilcox,
Björn Kieslich,
Manuel Jankovic,
Caroline Wilde,
Susanne Horn,
Norbert Sträter,
Ines Liebscher,
Torsten Schöneberg,
David Fenyo,
Thomas A. Neubert,
Dimitris G. Placantonakis
Affiliations
Joshua D. Frenster
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Corresponding author
Hediye Erdjument-Bromage
Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, NYU Grossman School of Medicine, New York, NY 10016, USA
Gabriele Stephan
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
Niklas Ravn-Boess
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
Shuai Wang
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
Wenke Liu
Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
Devin Bready
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
Jordan Wilcox
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
Björn Kieslich
Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, University of Leipzig, 04103 Leipzig, Germany; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Manuel Jankovic
Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, University of Leipzig, 04103 Leipzig, Germany
Caroline Wilde
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Susanne Horn
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Norbert Sträter
Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, University of Leipzig, 04103 Leipzig, Germany
Ines Liebscher
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Torsten Schöneberg
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
David Fenyo
Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
Thomas A. Neubert
Department of Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, NYU Grossman School of Medicine, New York, NY 10016, USA
Dimitris G. Placantonakis
Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Brain and Spine Tumor Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA; Corresponding author
Summary: The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity proteomics to identify the transmembrane protein PTK7 as an extracellular binding partner of GPR133 in glioblastoma. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7’s anchoring in the plasma membrane. PTK7’s allosteric action on GPR133 signaling is additive with but topographically distinct from orthosteric activation by soluble peptide mimicking the endogenous tethered Stachel agonist. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this ligand-receptor interaction is relevant to the pathogenesis of glioblastoma and possibly other physiological processes in healthy tissues.
