title: Phorbol 12-myristate 13-acetate-induced release of the colony-stimulating factor 1 receptor cytoplasmic domain into the cytosol involves two separate cleavage events.
abstract: The colony-stimulating factor 1 (CSF-1) receptor is a protein-tyrosine kinase that regulates cell division, differentiation, and development. In response to phorbol 12-myristate 13-acetate (PMA), the CSF-1 receptor is subject to proteolytic processing. Use of chimeric receptors indicates that the CSF-1 receptor is cleaved at least two times, once in the extracellular domain and once in the transmembrane domain. Cleavage in the extracellular domain results in ectodomain shedding while the cytoplasmic domain remains associated with the membrane. Intramembrane cleavage depends on the sequence of the transmembrane domain and results in the release of the cytoplasmic domain. This process can be blocked by gamma-secretase inhibitors. The cytoplasmic domain localizes partially to the nucleus, displays limited stability, and is degraded by the proteosome. CSF-1 receptors are continuously subject to down-modulation and regulated intramembrane proteolysis (RIP). RIP is stimulated by granulocyte-macrophage-CSF, CSF-1, interleukin-2 (IL-2), IL-4, lipopolysaccharide, and PMA and may provide the CSF-1 receptor with an additional mechanism for signal transduction.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093-0601, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilhelmsen
authors.forename: Peter
authors.initials: P
authors.lastname: van der Geer
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D016184:Receptors, Colony-Stimulating Factor / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism*
chemical_list: D016184:Receptors, Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate