Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.
- Author:
Shokichi TSUKAMOTO
1
;
Masahiro TAKEUCHI
;
Takeharu KAWAGUCHI
;
Emi TOGASAKI
;
Atsuko YAMAZAKI
;
Yasumasa SUGITA
;
Tomoya MUTO
;
Shio SAKAI
;
Yusuke TAKEDA
;
Chikako OHWADA
;
Emiko SAKAIDA
;
Naomi SHIMIZU
;
Keigo NISHII
;
Meizi JIANG
;
Koutaro YOKOTE
;
Hideaki BUJO
;
Chiaki NAKASEKO
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords: ADAM17; CD9; LR11; TNF-alpha converting enzyme; Tetraspanin
- MeSH: ADAM Proteins/*metabolism; Antigens, CD9/genetics/*metabolism; Cell Line, Tumor; Humans; LDL-Receptor Related Proteins/genetics/*metabolism; Leukocytes/*metabolism; Macrophages/metabolism; Membrane Transport Proteins/genetics/*metabolism; Proteolysis
- From:Experimental & Molecular Medicine 2014;46(4):e89-
- CountryRepublic of Korea
- Language:English
- Abstract: 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-alpha 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.
