Biochemical Journal 2012-08-01

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

Young-Woong Kim, Jinah Park, Hyun-Ju Lee, So-Young Lee, Seong-Jin Kim

Index: Biochem. J. 445(3) , 403-11, (2012)

Full Text: HTML

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.


Related Compounds

  • Kifunensine

Related Articles:

A context-independent N-glycan signal targets the misfolded extracellular domain of Arabidopsis STRUBBELIG to endoplasmic-reticulum-associated degradation.

2014-12-15

[Biochem. J. 464(3) , 401-11, (2014)]

Synthesis of kifunensine thioanalogs and their inhibitory activities against HIV-RT and α-mannosidase.

2013-01-10

[Carbohydr. Res. 365 , 1-8, (2013)]

Evolution of cross-neutralizing antibody specificities to the CD4-BS and the carbohydrate cloak of the HIV Env in an HIV-1-infected subject.

2012-01-01

[PLoS ONE 7(11) , e49610, (2012)]

The unfolded protein response transducer ATF6 represents a novel transmembrane-type endoplasmic reticulum-associated degradation substrate requiring both mannose trimming and SEL1L protein.

2013-11-01

[J. Biol. Chem. 288(44) , 31517-27, (2013)]

Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation.

2008-05-01

[Hum. Mutat. 17 , 1214-21, (2008)]

More Articles...