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A secreted type of β1,6 N‐acetylglucosaminyltransferase V (GnT‐V), a novel angiogenesis inducer, is regulated by γ‐secretase
Author(s) -
Nakahara Susumu,
Saito Takashi,
Kondo Nami,
Moriwaki Kenta,
Noda Katsuhisa,
Ihara Shinji,
Takahashi Motoko,
Ide Yoshihito,
Gu Jianguo,
Inohara Hidenori,
Katayama Taiichi,
Tohyama Masaya,
Kubo Takeshi,
Taniguchi Naoyuki,
Miyoshi Eiji
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5066com
Subject(s) - secretion , transmembrane protein , transfection , angiogenesis , presenilin , biochemistry , glycosyltransferase , cleavage (geology) , biology , proteases , microbiology and biotechnology , golgi apparatus , amyloid precursor protein secretase , amyloid precursor protein , chemistry , gene , enzyme , cell , genetics , paleontology , receptor , fracture (geology) , medicine , disease , pathology , alzheimer's disease
Glycosyltransferases are present in the Golgi apparatus in a membrane‐bound form and are released from cells after cleavage by certain proteases. β1,6‐N‐Acetylglucosaminyltransferase V (GnT‐V), which is cleaved and secreted from the cells, is involved in the biosynthesis of β1–6GlcNAc branching on N‐ glycans and has been implicated in tumor progression and metastasis. We recently reported that a secreted type of GnT‐V (soluble GnT‐V) itself could promote angiogenesis, which is completely different from its original function as a glycosyltransferase, and this might play a role in tumor invasion. In this study, to explore the molecular basis for this functional glycosyl‐transferase secretion, its cleavage site was examined and the protease(s) involved in that cleavage were identified. The NH2‐terminal protein sequence of purified soluble GnT‐V (~100 kDa) from GnT‐V‐overex‐pressed cells revealed that its terminus started at His31, located at the boundary position between the transmembrane and stem regions. This secretion was not inhibited by a single amino acid mutation at the cleavage site (Leu 29 , Leu 30 to Asp, His 31 to Ala), but specifically inhibited by addition of DFK‐167, a γ‐secretase inhibitor, suggesting that γ‐secretase is a plausible protease for secretion processing. In addition, transfection of the gene of familial Alzheimer's disease (FAD)‐ linked presenilin‐1, a component of γ‐secretase, in‐ creased the secretion rate of endogenous GnT‐V; the secretion of soluble GnT‐V (~100 kDa) was completely inhibited in presenilin‐1/2 double‐deficient cells, which have no γ‐secretase activity. Collectively, these results demonstrate that Golgi‐resident GnT‐V is cleaved at the transmembrane region by γ‐secretase, and this might control tumor angiogenesis through a novel pathway.—Nakahara, S., Saito, T., Kondo, N., Moriwaki, K., Noda, K., Ihara, S., Takahashi, M., Ide, Y., Gu, J., Inohara, H., Katayama, T., Tohyama, M., Kubo, T., Taniguchi, N., Miyoshi, E. A secreted type of H1,6 N‐acetylglucosaminyltransferase V (GnT‐V), a novel angiogenesis inducer, is regulated by γ‐secretase. FASEB J. 20, 2451–2459 (2006)