Muc4/sialomucin complex (SMC) is a heterodimeric glycoprotein complex implicated in epithelial protection and overexpressed in some tumours. It is encoded by a single gene, and the two subunits are produced by proteolytic cleavage at a time before substantial O-glycosylation, near the time of transit from the endoplasmic reticulum to the Golgi. Although Muc4/SMC is translated as a membrane protein, it is produced as a soluble form in many epithelia. Transfection experiments using Cos-7, HBL-100 human epithelial, MCF-7 human breast tumour and HC11 mouse mammary cell lines showed that soluble rat Muc4/SMC is produced by a proteolytic cleavage mechanism and released by secretion from multiple cell lines, including both human and mouse normal epithelial cells and tumour cells. Similar transfection experiments demonstrated the same mechanism for the human analogue MUC4. Gel electrophoresis analyses of deglycosylated membrane and soluble transmembrane subunits and of the membrane-associated cleavage fragment indicated a released cleavage product of 25kDa, resulting from cleavage between two epidermal growth factor-like domains. Further evidence for this site was obtained from deletion mutants removing this region of the protein, which blocked secretion. Finally, pulse—chase analyses of Muc4/SMC biosynthesis indicated no kinetic difference between the timing of the cleavage to release the soluble form and that to produce the two subunits, indicating that the soluble form is created early in transit to the cell surface. These studies provide the first clear evidence that membrane mucins can be released from cells by an intracellular proteolytic mechanism that leads to secretion of the soluble form of the mucin.
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November 2002
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Research Article|
November 15 2002
Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysis
Masanobu KOMATSU;
Masanobu KOMATSU
Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33101, U.S.A.
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Maria E. ARANGO;
Maria E. ARANGO
Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33101, U.S.A.
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Kermit L. CARRAWAY
Kermit L. CARRAWAY
1
Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33101, U.S.A.
1To whom correspondence should be addressed, at Department of Cell Biology and Anatomy (R-124), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, U.S.A. (e-mail kcarrawa@med.miami.edu).
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Publisher: Portland Press Ltd
Received:
June 04 2002
Revision Received:
July 18 2002
Accepted:
August 20 2002
Accepted Manuscript online:
August 20 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 368 (1): 41–48.
Article history
Received:
June 04 2002
Revision Received:
July 18 2002
Accepted:
August 20 2002
Accepted Manuscript online:
August 20 2002
Citation
Masanobu KOMATSU, Maria E. ARANGO, Kermit L. CARRAWAY; Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysis. Biochem J 15 November 2002; 368 (1): 41–48. doi: https://doi.org/10.1042/bj20020862
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