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Supplemental Figures S1-S14 from Loss of NF2 Induces TGFβ Receptor 1–mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome

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posted on 2023-04-03, 16:00 authored by Jung-Hyun Cho, Ah-Young Oh, Soyoung Park, So-mi Kang, Min-Ho Yoon, Tae-Gyun Woo, Shin-Deok Hong, Jihwan Hwang, Nam-Chul Ha, Ho-Young Lee, Bum-Joon Park

Supplementary Figure S1. Loss of NF2 protects mechanical stress-induced cell death. Supplementary Figure S2. TβR1 is sensor of physical stimulation. Supplementary Figure S3. TβR1 kinase activity is required for RKIP and NF2 suppression. Supplementary Figure S4. Loss of NF2 induces unbalanced TβR1 and TβR2 expression. Supplementary Figure S5. TβR1-mediated oncogenic signal such as invasion can be blocked by TβR2. Supplementary Figure S6. NF2 blocks the binding between RKIP and TβR1. Supplementary Figure S7. TβR1 phosphorylates RKIP. Supplementary Figure S8. The effect of TβR1 kinase inhibitors on NF2-deficient cells. Supplementary Figure S9. The effect of several kinds of selective TβR1 inhibitors. Supplementary Figure S10. Gene expression analysis. Supplementary Figure S11. TEW7197 induces HEI-193 differentiation into Schwann cell. Supplementary Figure S12. Histological analysis in NF2 syndrome model mouse. Supplementary Figure S13. Mouse phenotype. Supplementary Figure S14. Effect of TEW7197 treatment on the primary tumor cells isolated from vehicle-treated NF2 syndrome model mouse.

Funding

National Research Foundation of Korea (NRF)

Korean government

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ARTICLE ABSTRACT

Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease, and there has been no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGFβ receptor 2 (TβR2) expression, and an overwhelming expression of TGFβ receptor 1 (TβR1) is activated by physical stimuli such as pressure or heavy materials. Activated TβR1 induces the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2-deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197 treatment induces the expression of lipid metabolism–related gene set, such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGFβ signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2-mutated advanced cancers. Mol Cancer Ther; 17(11); 2271–84. ©2018 AACR.

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