title: Human CD180 Transmits Signals via the PIM-1L Kinase.
abstract: Toll-like receptors (TLRs) are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a downstream signaling cascade. The CD180/MD1 molecular complex is an unusual member of the TLR family, since it lacks the components that are normally required for signal transduction by other TLRs. Therefore the CD180/MD 1 complex has been considered of being incapable of independently initiating cellular signals. Using chemogenetic approaches we identified specifically the membrane bound long form of PIM-1 kinase, PIM-1L as the mediator of CD180-dependent signaling. A dominant negative isoform of PIM-1L, but not of other PIM kinases, inhibited signaling elicited by cross-linking of CD180, and this effect was phenocopied by PIM inhibitors. PIM-1L was directed to the cell membrane by its N-terminal extension, where it colocalized and physically associated with CD180. Triggering CD180 also induced increased phosphorylation of the anti-apoptotic protein BAD in a PIM kinase-dependent fashion. Also in primary human B cells, which are the main cells expressing CD180 in man, cross-linking of CD180 by monoclonal antibodies stimulated cell survival and proliferation that was abrogated by specific inhibitors. By associating with PIM-1L, CD180 can thus obtain autonomous signaling capabilities, and this complex is then channeling inflammatory signals into B cell survival programs. Pharmacological inhibition of PIM-1 should therefore provide novel therapeutic options in diseases that respond to innate immune stimulation with subsequently increased B cell activity, such as lupus erythematosus or myasthenia gravis.
authors.affiliation: Autoimmune, Transplantation, and Inflammatory Diseases Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Egli
authors.affiliation: Autoimmune, Transplantation, and Inflammatory Diseases Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zajonz
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.affiliation: Autoimmune, Transplantation, and Inflammatory Diseases Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Schweighoffer
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C092722:CD180 protein, human; D016207:Cytokines; D051573:Proto-Oncogene Proteins c-pim-1