title: Identification and mutagenesis of the TACE and γ-secretase cleavage sites in the colony-stimulating factor 1 receptor.
abstract: Stimulation of macrophages with phorbolesters, bacterial DNA, or lipopolysaccharides causes regulated intramembrane proteolysis or RIPping of the CSF-1 receptor. This process involves TACE-mediated cleavage in the extracellular domain, followed by γ-secretase-mediated cleavage within the transmembrane region. In the current study, we have identified the TACE cleavage site, which is present twelve residues from the carboxy-terminal end of the extracellular domain. Replacement of fourteen residues at the end of the extracellular domain blocked TACE cleavage. In addition, we identified the γ-secretase cleavage site, which is present four residues from the carboxy-terminal end of the transmembrane region. Replacement of six residues surrounding this site strongly reduced intramembrane cleavage. Our results provide new insights into the molecular physiology of the CSF-1 receptor and contribute to our understanding of substrate selection by TACE and γ-secretase.
authors: Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-1030, USA.
authors: Arrash
authors: A
authors: Vahidi
authors: Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-1030, USA.
authors: Gary
authors: G
authors: Glenn
authors: Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-1030, USA. Electronic address: pvanderg@mail.sdsu.edu.
authors: Peter
authors: P
authors: van der Geer
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: Cleavage site selection; Ectodomain shedding; Intramembrane proteolysis; Protein-tyrosine kinase; Signal transduction