Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes

Exp Mol Med. 2014 Apr 4;46(4):e89. doi: 10.1038/emm.2013.161.


LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Cell Line, Tumor
  • Humans
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism*
  • Leukocytes / metabolism*
  • Macrophages / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Proteolysis
  • Tetraspanin 29 / genetics
  • Tetraspanin 29 / metabolism*


  • LDL-Receptor Related Proteins
  • Membrane Transport Proteins
  • SORL1 protein, human
  • Tetraspanin 29
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human