TGF-β sensitivity is determined by N-linked glycosylation of the type II TGF-β receptor.

Abstract

N-linked glycosylation is a critical determinant of protein structure and function, regulating processes such as protein folding, stability and localization, ligand-receptor binding and intracellular signalling. TβRII [type II TGF-β (transforming growth factor β) receptor] plays a crucial role in the TGF-β signalling pathway. Although N-linked glycosylation of TβRII was first demonstrated over a decade ago, it was unclear how this modification influenced TβRII biology. In the present study, we show that inhibiting the N-linked glycosylation process successfully hinders binding of TGF-β1 to TβRII and subsequently renders cells resistant to TGF-β signalling. The lung cancer cell line A549, the gastric carcinoma cell line MKN1 and the immortal cell line HEK (human embryonic kidney)-293 exhibit reduced TGF-β signalling when either treated with two inhibitors, including tunicamycin (a potent N-linked glycosylation inhibitor) and kifunensine [an inhibitor of ER (endoplasmic reticulum) and Golgi mannosidase I family members], or introduced with a non-glycosylated mutant version of TβRII. We demonstrate that defective N-linked glycosylation prevents TβRII proteins from being transported to the cell surface. Moreover, we clearly show that not only the complex type, but also a high-mannose type, of TβRII can be localized on the cell surface. Collectively, these findings demonstrate that N-linked glycosylation is essentially required for the successful cell surface transportation of TβRII, suggesting a novel mechanism by which the TGF-β sensitivity can be regulated by N-linked glycosylation levels of TβRII.

• Authors: Young-Woong Kim, Jinah Park, Hyun-Ju Lee, So-Young Lee, Seong-Jin Kim
• Journal: The Biochemical journal (Biochem J) Vol. 445 Issue 3 Pg. 403-11 (Aug 01 2012) ISSN: 1470-8728 [Electronic] England
• PMID: 22571197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Receptors, Transforming Growth Factor beta
• Recombinant Proteins
• Transforming Growth Factor beta
• kifunensine
• Tunicamycin
• Asparagine
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Alkaloids (pharmacology)
• Amino Acid Sequence
• Amino Acid Substitution
• Asparagine (chemistry)
• Cell Line
• Cell Membrane (metabolism)
• Conserved Sequence
• Glycosylation (drug effects)
• HEK293 Cells
• HeLa Cells
• Hep G2 Cells
• Humans
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Protein Serine-Threonine Kinases (chemistry, genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (chemistry, genetics, metabolism)
• Recombinant Proteins (chemistry, genetics, metabolism)
• Sequence Homology, Amino Acid
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (metabolism)
• Tunicamycin (pharmacology)