Reactome | GSK3B-mediated proteasomal degradation of PD-L1(CD274)

GSK3B-mediated proteasomal degradation of PD-L1(CD274)

Stable Identifier

R-HSA-9929356

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Immune System (Homo sapiens)

- Adaptive Immune System (Homo sapiens)
  - Regulation of T cell activation by CD28 family (Homo sapiens)
    - Co-inhibition by PD-1 (Homo sapiens)
      - Regulation of PD-L1(CD274) expression (Homo sapiens)
        
        Regulation of PD-L1(CD274) Post-translational modification (Homo sapiens)
        
        GSK3B-mediated proteasomal degradation of PD-L1(CD274) (Homo sapiens)

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GSK3B-mediated proteasomal degradation of PD-L1(CD274)

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Post-translational modifications (PTMs) of PD-L1 (CD274) play an important regulatory role in modulating immune tolerance in normal physiology. The same mechanism is hijacked by cancer cells to enable immune evasion (Hsu et al., 2018, Dai et al., 2022, Yu et al., 2021). PD-L1 protein levels are tightly controlled by multiple mechanisms such as phosphorylation, glycosylation, ubiquitination, etc. (Feng et al., 2023). GSK3B is a serine-threonine kinase known to be regulated by multiple growth factor signalling pathways like EGFR, WNT, etc. GSK3B is constitutively active and phosphorylation by upstream pathways inactivates its kinase activity. GSK3B regulates PD-L1 protein stability and glycosylation. GSK3B phosphorylation of PD-L1 at T180 and S184 induces proteasomal degradation of PD-L1 and inhibits its glycosylation. GSK3B-induced phosphorylation facilitates binding of PD-L1 with β-TrCP (BTRC), a substrate recognition subunit of the SCF E3 ubiquitin ligase complex, which promotes PD-L1 ubiquitination and routes it for proteasomal degradation (Li et al, 2016, Schulz et al., 2019). Moreover, MET phosphorylates GSK3B at tyrosine 56, resulting in GSK3B activation and promotion of PD-L1 degradation (Li etal, 2019).

Literature References

PubMed ID	Title	Journal	Year
30711629	MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1 Li, H, Li, CW, Li, X, Ding, Q, Guo, L, Liu, S, Liu, C, Lai, CC, Hsu, JM, Dong, Q, Xia, W, Hsu, JL, Yamaguchi, H, Du, Y, Lai, YJ, Sun, X, Koller, PB, Ye, Q, Hung, MC	Gastroenterology	2019
30728908	Increased PD-L1 expression in radioresistant HNSCC cell lines after irradiation affects cell proliferation due to inactivation of GSK-3beta Schulz, D, Stancev, I, Sorrentino, A, Menevse, AN, Beckhove, P, Brockhoff, G, Hautmann, MG, Reichert, TE, Bauer, RJ, Ettl, T	Oncotarget	2019
27572267	Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity Li, CW, Lim, SO, Xia, W, Lee, HH, Chan, LC, Kuo, CW, Khoo, KH, Chang, SS, Cha, JH, Kim, T, Hsu, JL, Wu, Y, Hsu, JM, Yamaguchi, H, Ding, Q, Wang, Y, Yao, J, Lee, CC, Wu, HJ, Sahin, AA, Allison, JP, Yu, D, Hortobagyi, GN, Hung, MC	Nat Commun	2016
30442814	Posttranslational Modifications of PD-L1 and Their Applications in Cancer Therapy Hsu, JM, Li, CW, Lai, YJ, Hung, MC	Cancer Res	2018
34829931	Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave Yu, X, Li, W, Young, KH, Li, Y	Biomedicines	2021
37554324	Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy Feng, C, Zhang, L, Chang, X, Qin, D, Zhang, T	Front Immunol	2023
33831533	Post-translational regulations of PD-L1 and PD-1: Mechanisms and opportunities for combined immunotherapy Dai, X, Gao, Y, Wei, W	Semin Cancer Biol	2022