title: Transmembrane chemokines act as receptors in a novel mechanism termed inverse signaling.
abstract: The transmembrane chemokines CX3CL1/fractalkine and CXCL16 are widely expressed in different types of tumors, often without an appropriate expression of their classical receptors. We observed that receptor-negative cancer cells could be stimulated by the soluble chemokines. Searching for alternative receptors we detected that all cells expressing or transfected with transmembrane chemokine ligands bound the soluble chemokines with high affinity and responded by phosphorylation of intracellular kinases, enhanced proliferation and anti-apoptosis. This activity requires the intracellular domain and apparently the dimerization of the transmembrane chemokine ligand. Thus, shed soluble chemokines can generate auto- or paracrine signals by binding and activating their transmembrane forms. We term this novel mechanism "inverse signaling". We suppose that inverse signaling is an autocrine feedback and fine-tuning system in the communication between cells that in tumors supports stabilization and proliferation.
authors.affiliation: Department of Anatomy, University of Kiel, Kiel, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hattermann
authors.affiliation: Department of Anatomy, University of Kiel, Kiel, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Gebhardt
authors.affiliation: Department of Structural Biology, Institute of Zoology, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Krossa
authors.affiliation: Institute for Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Department of Anatomy, University of Kiel, Kiel, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Department of Neurosurgery, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
authors.affiliation: Department of Anatomy, University of Kiel, Kiel, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mentlein
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D051116:Receptors, Scavenger / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515538:CX3CL1 protein, human; C423727:CXCL16 protein, human; D054428:Chemokine CX3CL1; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D051116:Receptors, Scavenger
keywords: Cellular communication; Chemokines; cell biology; human; receptors; signal transduction