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TGF-? sensitivity is determined by N-linked glycosylation of the type II TGF-? 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. T?RII [type II TGF-? (transforming growth factor ?) receptor] plays a crucial role in the TGF-? signalling pathway. Although N-linked glycosylation of T?RII was first demonstrated over a decade ago, it was unclear how this modification influenced T?RII biology. In the present study, we show that inhibiting the N-linked glycosylation process successfully hinders binding of TGF-?1 to T?RII and subsequently renders cells resistant to TGF-? 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-? 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 T?RII. We demonstrate that defective N-linked glycosylation prevents T?RII 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 T?RII 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 T?RII, suggesting a novel mechanism by which the TGF-? sensitivity can be regulated by N-linked glycosylation levels of T?RII.

SUBMITTER: Kim YW

PROVIDER: S-EPMC3462611 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Kim Young-Woong YW Park Jinah J Lee Hyun-Ju HJ Lee So-Young SY Kim Seong-Jin SJ

The Biochemical journal 20120801 3

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 s ...[more]

PMID: 22571197

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Project description:BackgroundRadiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated.MethodsIn this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients' samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry.ResultsALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients.ConclusionOur results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

Dataset Information

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

Publications

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

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