Mechanistic insights into ectodomain shedding: Susceptibility of CADM1 adhesion molecule is determined by alternative splicing and O-glycosylation

Kyoko Shirakabe, Takuya Omura, Yoshio Shibagaki, Emiko Mihara, Keiichi Homma, Yukinari Kato, Akihiko Yoshimura, Yoshinori Murakami, Junichi Takagi, Seisuke Hattori, Yoshihiro Ogawa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Ectodomain shedding (shedding) is a post-translational modification, which liberates the extracellular domain of membrane proteins through juxtamembrane processing executed mainly by the ADAM (a disintegrin and metalloprotease) family of metalloproteases. Because shedding alters characteristics of cells in a rapid and irreversible manner, it should be strictly regulated. However, the molecular mechanisms determining membrane protein susceptibility to shedding (shedding susceptibility) are largely unknown. Here we report that alternative splicing can give rise to both shedding-susceptible and shedding-resistant CADM1 (cell adhesion molecule 1) variant proteins. We further show that O-glycans adjacent to the shedding cleavage site interfere with CADM1 shedding, and the only 33-bp alternative exon confers shedding susceptibility to CADM1 by inserting five non-glycosylatable amino acids between interfering O-glycans and the shedding cleavage site. These results demonstrate that shedding susceptibility of membrane protein can be determined at two different levels of its biosynthesis pathway, alternative splicing and O-glycosylation.

Original languageEnglish
Article number46174
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 2017 Apr 10

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Alternative Splicing
Cell Adhesion Molecules
Glycosylation
Membrane Proteins
Metalloproteases
Polysaccharides
Disintegrins
Post Translational Protein Processing
Exons
Amino Acids
Proteins

ASJC Scopus subject areas

  • General

Cite this

Mechanistic insights into ectodomain shedding : Susceptibility of CADM1 adhesion molecule is determined by alternative splicing and O-glycosylation. / Shirakabe, Kyoko; Omura, Takuya; Shibagaki, Yoshio; Mihara, Emiko; Homma, Keiichi; Kato, Yukinari; Yoshimura, Akihiko; Murakami, Yoshinori; Takagi, Junichi; Hattori, Seisuke; Ogawa, Yoshihiro.

In: Scientific Reports, Vol. 7, 46174, 10.04.2017.

Research output: Contribution to journalArticle

Shirakabe, K, Omura, T, Shibagaki, Y, Mihara, E, Homma, K, Kato, Y, Yoshimura, A, Murakami, Y, Takagi, J, Hattori, S & Ogawa, Y 2017, 'Mechanistic insights into ectodomain shedding: Susceptibility of CADM1 adhesion molecule is determined by alternative splicing and O-glycosylation', Scientific Reports, vol. 7, 46174. https://doi.org/10.1038/srep46174
Shirakabe, Kyoko ; Omura, Takuya ; Shibagaki, Yoshio ; Mihara, Emiko ; Homma, Keiichi ; Kato, Yukinari ; Yoshimura, Akihiko ; Murakami, Yoshinori ; Takagi, Junichi ; Hattori, Seisuke ; Ogawa, Yoshihiro. / Mechanistic insights into ectodomain shedding : Susceptibility of CADM1 adhesion molecule is determined by alternative splicing and O-glycosylation. In: Scientific Reports. 2017 ; Vol. 7.
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